Alexandre Corthay1,2,3*- 1Tumor Immunology Group, Department of Pathology, Oslo University Hospital Rikshospitalet, Oslo, Norway
- 2Department of Biosciences, University of Oslo, Oslo, Norway
- 3Centre for Immune Regulation, University of Oslo, Oslo, Norway
The importance of the immune system in conferring protection against pathogens like viruses, bacteria, and parasitic worms is well established. In contrast, there is a long-lasting debate on whether cancer prevention is a primary function of the immune system. The concept of immunological surveillance of cancer was developed by Lewis Thomas and Frank Macfarlane Burnet more than 50 years ago. We are still lacking convincing data illustrating immunological eradication of precancerous lesions in vivo. Here, I present eight types of evidence in support of the cancer immunosurveillance hypothesis. First, primary immunodeficiency in mice and humans is associated with increased cancer risk. Second, organ transplant recipients, who are treated with immunosuppressive drugs, are more prone to cancer development. Third, acquired immunodeficiency due to infection by human immunodeficiency virus (HIV-1) leads to elevated risk of cancer. Fourth, the quantity and quality of the immune cell infiltrate found in human primary tumors represent an independent prognostic factor for patient survival. Fifth, cancer cells harbor mutations in protein-coding genes that are specifically recognized by the adaptive immune system. Sixth, cancer cells selectively accumulate mutations to evade immune destruction (“immunoediting”). Seventh, lymphocytes bearing the NKG2D receptor are able to recognize and eliminate stressed premalignant cells. Eighth, a promising strategy to treat cancer consists in potentiating the naturally occurring immune response of the patient, through blockade of the immune checkpoint molecules CTLA-4, PD-1, or PD-L1. Thus, there are compelling pieces of evidence that a primary function of the immune system is to confer protection against cancer.
Introduction
Lewis Thomas and Frank Macfarlane Burnet proposed the concept of immunological surveillance of cancer more than five decades ago (1–4). It was defined by Burnet as follows: “In large long-lived animals, like most of the warm-blooded vertebrates, inheritable genetic changes must be common in somatic cells and a proportion of these changes will represent a step toward malignancy. It is an evolutionary necessity that there should be some mechanism for eliminating or inactivating such potentially dangerous mutant cells and it is postulated that this mechanism is of immunological character” (1). More than 50 years after Burnet proposed his theory, the immunological scientific community remains largely divided with both proponents [e.g., Ref. (5, 6)] and opponents [e.g., Ref. (7, 8)] of the cancer immunosurveillance hypothesis. In fact, an opposite and very influential concept was proposed in 2001 by Frances Balkwill and Alberto Mantovani, who suggested that inflammatory immune cells and cytokines found in tumors may promote rather than suppress tumor growth (9, 10). Although, we are currently lacking convincing data illustrating immunological eradication of precancerous lesions in vivo, there are strong indications that a primary function of the immune system is indeed to prevent cancer. Here, I present eight types of evidence in support of the cancer immunosurveillance hypothesis.
Primary Immunodeficiency in Humans and Mice is Associated with Increased Cancer Risk
As Burnet himself pointed out, an implication of the cancer immunosurveillance hypothesis is that immunodeficiency should be associated with increased likelihood of neoplasia (1). Immunodeficiencies can be divided in two main types: primary (inborn) immunodeficiencies, which are caused by genetic defects and whose incidence is approximately 1:10,000 births; and secondary immunodeficiencies, which are induced by immunosuppressive medication or viral infection and which are much more common. In accordance with Burnet’s prediction, severe primary immunodeficiencies have been reported to be associated with increased risk of malignancy (11–14). For instance, patients with defective humoral immunity due to common variable immunodeficiency (CVID) had increased incidence of lymphoma and epithelial tumors of the stomach, breast, bladder, and cervix (12, 15). Selective immunoglobulin A (IgA) deficiency was associated with a high incidence of gastric carcinomas (15). Moreover, patients with X-linked immunodeficiency with hyper-IgM, caused by mutations in the CD40 ligand molecule, had a high incidence of tumors of the pancreas and liver (16). However, it remains unclear to what extent primary immunodeficiency in humans leads to increased cancer development, due to the relatively low number of patients investigated.
Gene-targeted mice, which selectively lack key components of the immune system have been extensively used to experimentally test the effect of well-defined primary immunodeficiencies on cancer development [reviewed in Ref. (17)]. Mice which lacked both T and B cells, due to a deficiency in the recombination-activating gene 2 (RAG2), were more susceptible to spontaneous and carcinogen-induced carcinomas (18). Mice lacking γδ T cells were highly susceptible to multiple regimens of cutaneous carcinogenesis (19). The cytokines interferon-α/β (IFN-α/β) and IFN-γ were shown to protect mice against spontaneous and carcinogen-induced malignancy (18, 20–22). Moreover, the molecule perforin, which is used by cytotoxic lymphocytes to kill target cells, was reported to be important for surveillance of spontaneous lymphoma (23). Collectively, the human and mouse data reveal a consistent association between primary immunodeficiency and increased incidence of various types of cancer.
Organ Transplant Recipients are More Prone to Cancer Development
A breakthrough in organ transplantation was the discovery of immunosuppressive drugs such as cyclosporine A, which prevent organ rejection by the adaptive immune system (24). Immunosuppressive medication is now standard treatment after organ transplantation. Life-long treatment of thousands of transplanted patients with immunosuppressive drugs was defined by Thomas as a “human experiment” to test the cancer immunosurveillance hypothesis (4). Already in 1973, an international registry-based study of renal-transplant recipients from 30 countries revealed that transplantation was associated with increased risk of developing cancer, in particular lymphoma (25). A large cohort investigation of cancer risk after organ transplantation was performed in the Nordic countries, in homogeneous populations with well-documented cancer incidence, on nearly 6000 kidney recipients (26). A two to fivefold excess risk was reported for cancers of the colon, larynx, lung, bladder, prostate, and testis. Strikingly high risks, 10-fold to 30-fold above normally expected levels, were observed for cancers of the lip, skin (non-melanoma), kidney, endocrine glands, cervix, and for non-Hodgkin’s lymphoma (26). Another large study of kidney transplantation in 200,000 patients from 42 countries reported that the risk of developing lymphoma was 12-fold higher for transplant recipients than that in a matched non-transplanted population (27). Notably, the majority of posttransplant lymphomas were associated with infection with Epstein–Barr virus (EBV), which primarily infects B cells and is known to cause B cell transformation (28). Thus, most lymphomas arising in transplant patients were likely to be a secondary event resulting from reduced antiviral immunity, rather than a direct effect of reduced antitumor immunity. However, lymphomas not associated with EBV infection have also been reported after transplantation (29). An investigation of 175,000 solid organ transplants in the USA revealed that increased cancer risk occurred not only after kidney transplantation but also after liver, heart, and lung transplantation (30). Risk was increased for 32 different malignancies, some related to known infections (e.g., anal cancer and Kaposi sarcoma) and others unrelated to infections (e.g., lung cancer and melanoma). The most common malignancies with elevated risk were non-Hodgkin lymphoma and cancers of the lungs (30).
Very high rates of non-melanoma skin cancers have been reported for Swedish (20–40%) and Australian (70%) populations 20 years after transplantation (31–33). Cutaneous types of human papillomaviruses have been suggested to be the cause of non-melanoma skin cancers such as squamous cell carcinoma in immunosuppressed patients, but the epidemiological pieces of evidence remain inconsistent (34). Strikingly, non-melanoma skin tumors in the renal-transplant population of Queensland, Australia, were reported to arise predominantly on chronically sun-exposed skin (head, neck, and distal limbs), strongly suggesting a causative role of ultraviolet (UV) light rather than oncogenic viruses (33). Thus, life-long treatment of organ transplant recipients with immunosuppressive drugs leads to increased risk of developing many different types of cancer, some related to known infections and others unrelated.
Immunosuppression Induced by Infection by Human Immunodeficiency Virus Type 1 Leads to Elevated Risk for Cancer
The HIV-1 virus causes acquired immunodeficiency by selectively infecting and killing CD4+ T cells. Accordingly, HIV-infected patients, receiving or not antiviral treatments, possess reduced levels of CD4+ T cells compared to non-infected individuals. HIV-infected individuals have elevated risk for cancer linked to oncogenic viruses such as Kaposi sarcoma (caused by human herpes virus 8), Hodgkin’s and non-Hodgkin’s lymphoma (EBV), anal and cervical cancer (human papilloma virus), and liver cancer (hepatitis B and C viruses). Kaposi sarcoma, non-Hodgkin’s lymphoma and cervical cancer are particularly frequent and are considered as acquired immunodeficiency syndrome (AIDS)-defining cancers (35). However, several cancers that are not linked to oncogenic viruses, like lung cancer and multiple myeloma, are also more frequent in patients with HIV (35, 36). Lung cancer is the most common non-AIDS-defining cancer and a leading cause of mortality among HIV-infected individuals (37). For the majority of patients with lung cancer, malignant transformation is known to be caused by carcinogens present in cigarette smoke. Higher smoking rates have been reported for HIV-infected populations. After controlling for potential confounders including smoking, a large cohort study of veterans (with 37,000 HIV-infected patients and 75,000 healthy controls) concluded that HIV was an independent risk factor for incident lung cancer (37). Importantly, cancer incidence in HIV-infected individuals was found to be inversely related to CD4+ T cell counts in blood, which supports the association between immunosuppression and increased cancer risk (38). For instance, the risk of lung cancer was doubled by CD4+ T counts in the range of 350–499 cells per microliter blood compared to normal counts ≥500, and continued to increase as the CD4+ T cell count fell (38). Thus, acquired immunodeficiency by HIV infection, which selectively depletes CD4+ T cells, leads to increased risk of developing many different types of cancer, some related to known infections, and others unrelated.
Quantity and Quality of the Immune Cell Infiltrate in Human Primary Tumors Represent an Independent Prognostic Factor for Patient Survival
All solid tumors are infiltrated by a variety of immune cells. For many types of human cancers, an association has been reported between the type, density, and location of immune cells within the primary tumor and the clinical outcome [reviewed in Ref. (39)]. The number of intratumoral CD3+ T cells was shown to positively correlate with longer survival of patients with epithelial ovarian and colorectal cancers (40, 41). A high number of stromal CD4+ T cells were found to represent an independent positive prognostic factor in non-small cell lung cancer (42). Tumor-infiltrating CD8+ cytotoxic T cells were shown to predict clinical outcome in colon, lung, and breast cancers (42–45). Concurrent infiltration by both CD4+ and CD8+ T cells was reported to represent a favorable prognostic factor in esophageal squamous cell carcinoma and non-small cell lung cancer, suggesting that both cell types cooperate to fight cancer (46, 47). Among all CD4+ T cell subsets, Th1 cells seem to be particularly advantageous, as reported for colorectal, liver, and breast cancers (39, 40, 48, 49). In patients with gastrointestinal stromal tumors (GIST), the intratumoral density of CD3+ T cells and NKp46+ natural killer (NK) cells were found to represent two independent prognostic factors for progression-free survival (50). Notably, NK and T cells were detected in distinct areas of tumor sections, suggesting that both cell types contributed independently to GIST immunosurveillance (50). Furthermore, a high tumor infiltration by CD68+ macrophages was associated with prolonged survival in prostate, lung, and colon cancers (43, 51–54). Thus, for various types of human cancers, the quantity and the quality of the immune response within the primary tumor appear to represent an independent predictor for patient survival. This correlation between immunological data and clinical outcome strongly suggests that the immune system of the patient had naturally mounted an antitumor immune response before any treatment had started. The efficiency of this response presumably varies from patient to patient, thereby critically influencing survival.
Cancer Cells Harbor Mutations in Protein-Coding Genes that are Specifically Recognized by the Adaptive Immune System
Cancer cells originate from normal cells that have accumulated “driver” mutations, which either activate oncogenes by dominant gain of function or inactivate tumor suppressor genes by recessive loss of function. A typical tumor contains two to eight of these driver mutations (55). Cancer cells also accumulate “passenger” mutations, which do not contribute to tumorigenesis. Genome-wide sequencing studies have provided detailed information about somatic mutations in various types of cancers. For common solid tumors such as breast, colon, brain, and pancreas cancers, an average of 30–60 non-synonymous mutations in protein-coding genes was observed (56–59). Most of these mutations (95%) were single-nucleotide substitutions, whereas the remainder was deletions or insertions (55). Metastatic melanoma and non-small cell lung carcinoma, which represent two types of cancers caused by potent mutagens (UV light and cigarette smoke, respectively), had a higher mutation rate with ~150 mutations per tumor (60, 61). Pediatric tumors and leukemias had the fewest mutations with ~10 mutations per tumor on average (55). Thus, it is now established that tumor cells in most cancer types harbor numerous non-synonymous mutations in protein-coding genes.
Driver and passenger mutations, which alter the normal amino acid sequence of proteins, may potentially be recognized by the adaptive immune system. A number of studies have revealed that tumor-specific antigens created by mutations can be recognized either by the T cells or the B cells of the patient. For instance in melanoma, CD4+ T cells were found that recognized a tumor-specific antigen generated by a non-synonymous point mutation in the gene coding for triosephosphate isomerase (62). Another antigen recognized by CD4+ T cells in melanoma had been generated by a chromosomal rearrangement resulting in a fusion of a low density lipid receptor gene with a fucosyltransferase gene (63). In colorectal cancer with microsatellite instability phenotype, CD4+ T cells were identified that recognized a frameshift mutation in the transforming growth factor β receptor II (TGFβRII) (64). In a melanoma patient, the tumor suppressor p16INK4a with a point mutation was specifically recognized by cytotoxic CD8+ T cells (65). In non-small cell lung cancer, several CD8+ T cell epitopes created by point mutations have been reported (66–68). Moreover, in chronic myeloid leukemia, cytotoxic CD8+ T cells specific for a BCR-ABL fusion protein (resulting from the fusion of BCR and ABL genes) were found (69). Tumor-specific IgG antibodies are common in the serum of cancer patients, as revealed by serological identification of antigens by recombinant expression cloning (SEREX) technology (70). This powerful method has allowed the identification of over 2000 tumor antigens recognized by autologous IgG, including the p53 tumor suppressor modified by a point mutation (71). Collectively, these studies demonstrate that the adaptive immune system is able to detect cancer by specifically recognizing the mutated proteins of the malignant cells.
Cancer Cells Selectively Accumulate Mutations to Evade Immune Destruction
Recognition of cancer cells by tumor-specific CD8+ T cells is achieved by the presentation of antigenic peptides from mutated proteins on major histocompatibility complex (MHC) class I molecules on the surface of cancer cells. In order to avoid recognition and the resulting elimination by CD8+ T cells, cancer cells often mutate key genes of the MHC class I antigen presentation pathway. Downregulation of surface MHC class I molecules is a common feature of human cancer cells [reviewed in Ref. (72)]. Several mechanisms have been reported, including mutations in the β2-microglobulin gene, which is required for MHC class I molecule expression on the cell surface (73, 74). MHC haplotype loss in various human tumors was shown to be caused by complete or partial loss of chromosome 6, which harbor all MHC class I and class II genes (except for β2-microglobulin) (75). On the basis of its mutation pattern in cancer cells, β2-microglobulin was recently included in a list of 74 tumor suppressor genes (55). A recent study analyzed somatic point mutations in exon sequences from 4742 human cancers across 21 cancer types (76). Based on mutation frequency and pattern, 254 “cancer genes” were identified, including four genes belonging to the MHC class I antigen presentation pathway (β2-microglobulin, HLA-A, HLA-B, and TAP1), as well as the CD1D gene, which is involved in the presentation of lipid antigens to NK T cells (76). Hence, several mutations frequently observed in cancer cells are likely to result from selective pressure to evade the immune attack, in particular by cytotoxic CD8+ T cells and NK T cells.
Another strategy used by cancer cells to avoid the immune response consists of secreting immunosuppressive cytokines such as transforming growth factor β (TGF-β) and interleukin 10 (IL-10). In contrast to normal cells, which produce very little, malignant cells often secrete large amounts of TGF-β and IL-10 [reviewed in Ref. (77)]. Both cytokines have various effects on non-transformed cells present in the tumor mass, most notably the inhibition of immune cell functions. For several types of cancers, elevated serum levels of TGF-β or IL-10 have been reported to be associated with worse prognosis [reviewed in Ref. (77)]. Surprisingly, TGF-β can function both as a tumor suppressor and a tumor promoter, this duality being known as the TGF-β paradox. In early stage tumors, TGF-β is a potent inducer of growth arrest. In advanced stage malignant cells, TGF-β signaling pathways are severely dysregulated, and TGF-β promotes tumor growth [reviewed in Ref. (78)]. Thus, cancer cells often produce abnormally high levels of immunosuppressive cytokines, which strongly suggests that dampening immunity is a prerequisite for tumor growth.
Experiments with immunodeficient mice have demonstrated that the immune system may exert a strong selective pressure on the cancer cells. By using the chemical carcinogen methylcholanthrene, sarcomas were induced either in wild-type mice or in RAG2-deficient mice, which lack both T and B cells (18). When transplanted into RAG2-deficient mice, all sarcomas grew progressively with equivalent kinetics. In contrast, when the tumor cells were injected into immunocompetent wild-type hosts, all sarcomas from wild-type mice grew progressively, while 8 of 20 (40%) sarcomas from RAG2-deficient mice were rejected (18). These data strongly suggest that in wild-type mice, there was selection of tumor cells that were more capable of surviving in an immunocompetent host. This provides an explanation for the apparent paradox of tumor formation in immunologically intact individuals. Based on these findings, Robert Schreiber and coworkers introduced the term “cancer immunoediting,” which was further developed into a general theory, to describe the sculpting actions of the immune response on developing tumors in immunocompetent individuals (18, 79).
Lymphocytes Bearing the NKG2D Receptor are Able to Recognize and Eliminate Stressed Premalignant Cells
NK cells are innate lymphocytes that can kill malignant or infected cells. All NK cells and some T cells express the NKG2D molecule on the cell surface. NKG2D is an activating receptor, which serves as a major recognition receptor for detection and elimination of transformed cells (80). The ligands for NKG2D are self proteins that are poorly expressed by normal resting cells but upregulated on the surface of stressed cells. NKG2D ligands in humans include MICA, MICB, and six different ULBP proteins (81). In mice, NKG2D ligands include MULT1, five isoforms of RAE-1, and three isoforms of the H60 proteins (82). In humans, cells that express NKG2D ligands may be recognized and killed by either NK cells or γδ T cells in a process called lymphoid stress surveillance (83).
NKG2D ligands were shown to be upregulated in normal cells after treatment with DNA-damaging agents like ionizing radiations and UV light (84). It was concluded that the DNA damage response, which was known to arrest the cell cycle and enhance DNA repair, may also participate in alerting the immune system to the presence of potentially dangerous cells (84). Several studies suggested that expression of NKG2D ligands on transformed cells may be directly induced by oncogenes. For example, the BCR-ABL fusion oncogene was reported to control the expression of MICA in chronic myelogenous leukemia cells at the posttranscriptional level (85). Activation of the Ras oncogene was shown to upregulate the expression of RAE-1α/β in mouse cells, and ULBP1–3 and MICA/B in human cells (86). In a recent study, surface upregulation of NKG2D ligands by human epithelial cells in response to UV irradiation, osmotic shock, or oxidative stress, was shown to depend on the activation of the epidermal growth factor receptor (EGFR) (87). The EGFR pathway is frequently dysregulated in human cancer and it was proposed that activation of EGFR may regulate the immunological visibility of stressed premalignant cells (87). Surprisingly, several isoforms of RAE-1, like RAE-1ε, were found to be expressed not only by cancer cells, but also by some normal proliferating cells such as fibroblasts (88). The E2F transcription factor, which controls cell cycle entry, was shown to regulate RAE-1ε expression. These data suggest that NKG2D-bearing lymphocytes may control the proliferation of both normal and malignant cells (88).
MICA and MICB were found to be expressed by many, but not all, freshly isolated carcinomas of the lung, breast, kidney, ovary, prostate, colon, and liver (89, 90). Moreover, in vitro studies revealed that MICA and MICB contributed to the lysis of hepatocellular carcinoma cells by NK cells (90). The importance of NKG2D for cancer immunosurveillance in vivo gained support from experiments showing that cancer cells transfected with NKG2D ligands and injected into mice were rapidly rejected by NK cells and by CD8+ T cells (91, 92). Moreover, neutralization of NKG2D with blocking monoclonal antibodies rendered mice more susceptible to carcinogen-induced fibrocarcinoma (93). Gene-targeted mice deficient for NKG2D were shown to be more susceptible to the in situ development of prostate adenocarcinoma and B cell lymphoma (94). In humans, an association has been reported between polymorphisms of the NKG2D gene and susceptibility of developing liver and cervix cancers, supporting a protective role of NKG2D against these malignancies (95, 96). Thus, the expression of stress-induced endogenous molecules associated with cell transformation is used by the immune system to recognize and eliminate premalignant cells in mice and humans.
Promising Novel Strategy to Treat Cancer Consists in Potentiating the Naturally Occurring Immune Response of the Patient Through Blockade of Immune Checkpoint Molecules
Activation of a naïve T cell requires at least two signals: T cell receptor-mediated recognition of a cognate antigen (signal 1) and engagement of the costimulatory receptor CD28 (signal 2). Once activated, T cells upregulate on the cell surface two co-inhibitory molecules, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programed death 1 (PD-1). The function of these co-inhibitory molecules is to tightly regulate the immune response by containing excessive T cell activation. For the purpose of cancer immunotherapy, monoclonal antibodies have been generated to potentiate the ongoing antitumor immune response of the patient, through “immune checkpoint blockade” of CTLA-4, PD-1, or PD-1 ligand (PD-L1). The outcome of the initial clinical trials with these new treatments is remarkable (97).
In a phase 3, randomized trial, the CTLA-4 blocking antibody ipilimumab was shown to prolong survival of patients with previously treated metastatic melanoma by ~4 months (98). This was a breakthrough in the treatment of metastatic melanoma because no other therapy had previously been shown to prolong survival in a phase 3 controlled trial. Another phase 3 trial with previously untreated metastatic melanoma patients showed that the overall survival was significantly longer in the group receiving ipilimumab combined with the chemotherapy drug dacarbazine than in the group receiving dacarbazine plus placebo (11 vs. 9 months) (99). Moreover, higher survival rates after 3 years were observed in the ipilimumab–dacarbazine group compared to controls (21 vs. 12%) (99).
Although no phase 3 trial has yet been published based on PD-1 or PD-L1 blockade, phase 1 studies showed promising results. PD-1 checkpoint blockade was tested in a phase 1 trial on patients with several types of advanced cancer. Cumulative response rates (complete or partial responses) were 18% among patients with non-small cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable, 20 of 31 responses lasting 1 year or more in patients with 1 year or more of follow-up (100). In a phase 1 trial with anti-PD-L1 blocking antibodies, an objective response (complete or partial response) was observed in 9 of 52 patients with melanoma, 2 of 17 with renal-cell cancer, and 5 of 49 with non-small cell lung cancer. Responses lasted for 1 year or more in 8 of 16 patients with at least 1 year of follow-up (101). Finally, combined treatment of advanced melanoma was performed with both anti-CTLA-4 and anti-PD-1 blocking antibodies in a phase 1 trial. The objective response rate for all 53 treated patients in the concurrent-regimen group was as high as 40% (102). Thus, immune checkpoint blockade represents a promising new strategy to treat advanced cancer in humans. The success of this approach, which is based on potentiating the ongoing, naturally occurring antitumor immune response of the patient, provides another piece of evidence that fighting cancer is indeed a primary function of the immune system.
Concluding Remarks
As summarized in this review, the scientific literature over the past 50 years has provided strong support to the cancer immunosurveillance hypothesis. Thus, it appears that our immune system does not only naturally protect us against infectious non-self (pathogens) but also against malignant self (cancer). Many cell types belonging to both the innate (NK cells and macrophages) and the adaptive (T and B cells) immune systems seem to be involved in cancer control. Our current understanding on how the immune system fights cancer remains very fragmentary. There are pieces of evidence for two main strategies used by the immune system to distinguish cancer cells from normal cells. On one hand, the adaptive immune system recognizes altered (mutated) self proteins in malignant cells. On the other hand, NK cells and γδ T cells recognize stress-induced self molecules (NKG2D ligands) on transformed cells. Yet, cancer cells originate from normal cells and a main challenge for successful antitumor immunity is to restrain the destruction of normal cells (autoimmunity). In fact, a recent study suggested that autoimmune disease may occur as a result of an inaccurate antitumor immune response (103). Scleroderma is an autoimmune connective tissue disease in which patients make antibodies to a limited number of autoantigens, including the RNA polymerase III subunit, encoded by the POLR3A gene. In several patients who had both scleroderma and cancer, genetic alterations of the POLR3A locus were found in the malignant cells, suggesting that POLR3A mutations triggered an adaptive antitumor immune response, which cross-reacted with normal tissue, causing autoimmune disease (103).
Conflict of Interest Statement
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments
I thank Inger Øynebråten for critical reading of the manuscript. This work was supported by grants from the Research Council of Norway, the Southern and Eastern Norway Regional Health Authority, the Norwegian Cancer Society, Anders Jahre fund, and Henrik Homans Minde fund.
References
2. Burnet M. Cancer: a biological approach. III. Viruses associated with neoplastic conditions. IV. Practical applications. Br Med J (1957) 1:841–7. doi: 10.1136/bmj.1.5023.841
3. Thomas L. Discussion. In: Lawrence HS editor. Cellular and Humoral Aspects of the Hypersensitive States. New York: Hoeber-Harper (1959). p. 529–32.
5. Senovilla L, Vitale I, Martins I, Tailler M, Pailleret C, Michaud M, et al. An immunosurveillance mechanism controls cancer cell ploidy. Science (2012) 337:1678–84. doi:10.1126/science.1224922
6. Smyth MJ, Godfrey DI, Trapani JA. A fresh look at tumor immunosurveillance and immunotherapy. Nat Immunol (2001) 2:293–9. doi:10.1038/86297
7. Fuchs EJ, Matzinger P. Is cancer dangerous to the immune system? Semin Immunol (1996) 8:271–80. doi:10.1006/smim.1996.0035
8. Willimsky G, Blankenstein T. Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature (2005) 437:141–6. doi:10.1038/nature03954
9. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet (2001) 357:539–45. doi:10.1016/S0140-6736(00)04046-0
10. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature (2008) 454:436–44. doi:10.1038/nature07205
11. Gatti RA, Good RA. Occurrence of malignancy in immunodeficiency diseases. A literature review. Cancer (1971) 28:89–98. doi:10.1002/1097-0142(197107)28:1<89::AID-CNCR2820280117>3.0.CO;2-Q
12. Kinlen LJ, Webster AD, Bird AG, Haile R, Peto J, Soothill JF, et al. Prospective study of cancer in patients with hypogammaglobulinemia. Lancet (1985) 1:263–6. doi:10.1016/S0140-6736(85)91037-2
13. Salavoura K, Kolialexi A, Tsangaris G, Mavrou A. Development of cancer in patients with primary immunodeficiencies. Anticancer Res (2008) 28:1263–9.
14. van der Meer JW, Weening RS, Schellekens PT, van Munster IP, Nagengast FM. Colorectal cancer in patients with X-linked agammaglobulinemia. Lancet (1993) 341:1439–40. doi:10.1016/0140-6736(93)90883-I
15. Mueller BU, Pizzo PA. Cancer in children with primary or secondary immunodeficiencies. J Pediatr (1995) 126:1–10. doi:10.1016/S0022-3476(95)70491-4
16. Hayward AR, Levy J, Facchetti F, Notarangelo L, Ochs HD, Etzioni A, et al. Cholangiopathy and tumors of the pancreas, liver, and biliary tree in boys with X-linked immunodeficiency with hyper-IgM. J Immunol (1997) 158:977–83.
17. Swann JB, Smyth MJ. Immune surveillance of tumors. J Clin Invest (2007) 117:1137–46. doi:10.1172/JCI31405
18. Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, et al. IFN gamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature (2001) 410:1107–11. doi:10.1038/35074122
19. Girardi M, Oppenheim DE, Steele CR, Lewis JM, Glusac E, Filler R, et al. Regulation of cutaneous malignancy by gammadelta T cells. Science (2001) 294:605–9. doi:10.1126/science.1063916
20. Dunn GP, Bruce AT, Sheehan KC, Shankaran V, Uppaluri R, Bui JD, et al. A critical function for type I interferons in cancer immunoediting. Nat Immunol (2005) 6:722–9. doi:10.1038/ni1213
21. Kaplan DH, Shankaran V, Dighe AS, Stockert E, Aguet M, Old LJ, et al. Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci U S A (1998) 95:7556–61. doi:10.1073/pnas.95.13.7556
22. Street SE, Trapani JA, MacGregor D, Smyth MJ. Suppression of lymphoma and epithelial malignancies effected by interferon gamma. J Exp Med (2002) 196:129–34. doi:10.1084/jem.20020063
23. Smyth MJ, Thia KY, Street SE, MacGregor D, Godfrey DI, Trapani JA. Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. J Exp Med (2000) 192:755–60. doi:10.1084/jem.192.5.755
24. Calne RY, White DJ, Thiru S, Evans DB, McMaster P, Dunn DC, et al. Cyclosporin A in patients receiving renal allografts from cadaver donors. Lancet (1978) 2:1323–7. doi:10.1016/S0140-6736(78)91970-0
25. Hoover R, Fraumeni JF Jr. Risk of cancer in renal-transplant recipients. Lancet (1973) 2:55–7. doi:10.1016/S0140-6736(73)93256-X
26. Birkeland SA, Storm HH, Lamm LU, Barlow L, Blohme I, Forsberg B, et al. Cancer risk after renal transplantation in the Nordic countries, 1964-1986. Int J Cancer (1995) 60:183–9. doi:10.1002/ijc.2910600209
27. Opelz G, Dohler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant (2004) 4:222–30. doi:10.1111/j.1600-6143.2004.00451.x
28. List AF, Greco FA, Vogler LB. Lymphoproliferative diseases in immunocompromised hosts: the role of Epstein-Barr virus. J Clin Oncol (1987) 5: 1673–89.
29. Leblond V, Davi F, Charlotte F, Dorent R, Bitker MO, Sutton L, et al. Posttransplant lymphoproliferative disorders not associated with Epstein-Barr virus: a distinct entity? J Clin Oncol (1998) 16:2052–9.
30. Engels EA, Pfeiffer RM, Fraumeni JF Jr, Kasiske BL, Israni AK, Snyder JJ, et al. Spectrum of cancer risk among US solid organ transplant recipients. JAMA (2011) 306:1891–901. doi:10.1001/jama.2011.1592
31. Bouwes Bavinck JN, Hardie DR, Green A, Cutmore S, MacNaught A, O’Sullivan B, et al. The risk of skin cancer in renal transplant recipients in Queensland, Australia. A follow-up study. Transplantation (1996) 61:715–21. doi:10.1097/00007890-199603150-00008
32. Krynitz B, Edgren G, Lindelof B, Baecklund E, Brattstrom C, Wilczek H, et al. Risk of skin cancer and other malignancies in kidney, liver, heart and lung transplant recipients 1970 to 2008 – a Swedish population-based study. Int J Cancer (2013) 132:1429–38. doi:10.1002/ijc.27765
33. Ramsay HM, Fryer AA, Hawley CM, Smith AG, Harden PN. Non-melanoma skin cancer risk in the Queensland renal transplant population. Br J Dermatol (2002) 147:950–6. doi:10.1046/j.1365-2133.2002.04976.x
34. Schulz TF. Cancer and viral infections in immunocompromised individuals. Int J Cancer (2009) 125:1755–63. doi:10.1002/ijc.24741
35. Clifford GM, Polesel J, Rickenbach M, Dal Maso L, Keiser O, Kofler A, et al. Cancer risk in the Swiss HIV Cohort Study: associations with immunodeficiency, smoking, and highly active antiretroviral therapy. J Natl Cancer Inst (2005) 97:425–32. doi:10.1093/jnci/dji072
36. Shiels MS, Cole SR, Kirk GD, Poole C. A meta-analysis of the incidence of non-AIDS cancers in HIV-infected individuals. J Acquir Immune Defic Syndr (2009) 52:611–22. doi:10.1097/QAI.0b013e3181b327ca
37. Sigel K, Wisnivesky J, Gordon K, Dubrow R, Justice A, Brown ST, et al. HIV as an independent risk factor for incident lung cancer. AIDS (2012) 26:1017–25. doi:10.1097/QAD.0b013e328352d1ad
38. Guiguet M, Boue F, Cadranel J, Lang JM, Rosenthal E, Costagliola D. Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4): a Prospective Cohort Study. Lancet Oncol (2009) 10:1152–9. doi:10.1016/S1470-2045(09)70282-7
39. Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer (2012) 12:298–306. doi:10.1038/nrc3245
40. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science (2006) 313:1960–4. doi:10.1126/science.1129139
41. Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med (2003) 348:203–13. doi:10.1056/NEJMoa020177
42. Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund LT. Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. Clin Cancer Res (2008) 14:5220–7. doi:10.1158/1078-0432.CCR-08-0133
43. Kawai O, Ishii G, Kubota K, Murata Y, Naito Y, Mizuno T, et al. Predominant infiltration of macrophages and CD8(+) T Cells in cancer nests is a significant predictor of survival in stage IV nonsmall cell lung cancer. Cancer (2008) 113:1387–95. doi:10.1002/cncr.23712
44. Mahmoud SM, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AH, et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol (2011) 29:1949–55. doi:10.1200/JCO.2010.30.5037
45. Naito Y, Saito K, Shiiba K, Ohuchi A, Saigenji K, Nagura H, et al. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res (1998) 58:3491–4.
46. Cho Y, Miyamoto M, Kato K, Fukunaga A, Shichinohe T, Kawarada Y, et al. CD4+ and CD8+ T cells cooperate to improve prognosis of patients with esophageal squamous cell carcinoma. Cancer Res (2003) 63:1555–9.
47. Hiraoka K, Miyamoto M, Cho Y, Suzuoki M, Oshikiri T, Nakakubo Y, et al. Concurrent infiltration by CD8+ T cells and CD4+ T cells is a favourable prognostic factor in non-small-cell lung carcinoma. Br J Cancer (2006) 94:275–80. doi:10.1038/sj.bjc.6602934
48. Budhu A, Forgues M, Ye QH, Jia HL, He P, Zanetti KA, et al. Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell (2006) 10:99–111. doi:10.1016/j.ccr.2006.06.016
49. Kristensen VN, Vaske CJ, Ursini-Siegel J, Van Loo P, Nordgard SH, Sachidanandam R, et al. Integrated molecular profiles of invasive breast tumors and ductal carcinoma in situ (DCIS) reveal differential vascular and interleukin signaling. Proc Natl Acad Sci U S A (2012) 109:2802–7. doi:10.1073/pnas.1108781108
50. Rusakiewicz S, Semeraro M, Sarabi M, Desbois M, Locher C, Mendez R, et al. Immune infiltrates are prognostic factors in localized gastrointestinal stromal tumors. Cancer Res (2013) 73:3499–510. doi:10.1158/0008-5472.CAN-13-0371
51. Forssell J, Oberg A, Henriksson ML, Stenling R, Jung A, Palmqvist R. High macrophage infiltration along the tumor front correlates with improved survival in colon cancer. Clin Cancer Res (2007) 13:1472–9. doi:10.1158/1078-0432.CCR-06-2073
52. Kim DW, Min HS, Lee KH, Kim YJ, Oh DY, Jeon YK, et al. High tumour islet macrophage infiltration correlates with improved patient survival but not with EGFR mutations, gene copy number or protein expression in resected non-small cell lung cancer. Br J Cancer (2008) 98:1118–24. doi:10.1038/sj.bjc.6604256
53. Shimura S, Yang G, Ebara S, Wheeler TM, Frolov A, Thompson TC. Reduced infiltration of tumor-associated macrophages in human prostate cancer: association with cancer progression. Cancer Res (2000) 60:5857–61.
54. Welsh TJ, Green RH, Richardson D, Waller DA, O’Byrne KJ, Bradding P. Macrophage and mast-cell invasion of tumor cell islets confers a marked survival advantage in non-small-cell lung cancer. J Clin Oncol (2005) 23:8959–67. doi:10.1200/JCO.2005.01.4910
55. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW. Cancer genome landscapes. Science (2013) 339:1546–58. doi:10.1126/science.1235122
56. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science (2008) 321:1801–6. doi:10.1126/science.1164368
57. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, et al. An integrated genomic analysis of human glioblastoma multiforme. Science (2008) 321:1807–12. doi:10.1126/science.1164382
58. Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, et al. The consensus coding sequences of human breast and colorectal cancers. Science (2006) 314:268–74. doi:10.1126/science.1133427
59. Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, et al. The genomic landscapes of human breast and colorectal cancers. Science (2007) 318:1108–13. doi:10.1126/science.1145720
60. Govindan R, Ding L, Griffith M, Subramanian J, Dees ND, Kanchi KL, et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell (2012) 150:1121–34. doi:10.1016/j.cell.2012.08.024
61. Wei X, Walia V, Lin JC, Teer JK, Prickett TD, Gartner J, et al. Exome sequencing identifies GRIN2A as frequently mutated in melanoma. Nat Genet (2011) 43:442–6. doi:10.1038/ng.810
62. Wang RF, Wang X, Atwood AC, Topalian SL, Rosenberg SA. Cloning genes encoding MHC class II-restricted antigens: mutated CDC27 as a tumor antigen. Science (1999) 284:1351–4. doi:10.1126/science.284.5418.1351
63. Wang RF, Wang X, Rosenberg SA. Identification of a novel major histocompatibility complex class II-restricted tumor antigen resulting from a chromosomal rearrangement recognized by CD4(+) T cells. J Exp Med (1999) 189:1659–68. doi:10.1084/jem.189.10.1659
64. Saeterdal I, Bjorheim J, Lislerud K, Gjertsen MK, Bukholm IK, Olsen OC, et al. Frameshift-mutation-derived peptides as tumor-specific antigens in inherited and spontaneous colorectal cancer. Proc Natl Acad Sci U S A (2001) 98:13255–60. doi:10.1073/pnas.231326898
65. Wolfel T, Hauer M, Schneider J, Serrano M, Wolfel C, Klehmann-Hieb E, et al. A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science (1995) 269:1281–4. doi:10.1126/science.7652577
66. Echchakir H, Mami-Chouaib F, Vergnon I, Baurain JF, Karanikas V, Chouaib S, et al. A point mutation in the alpha-actinin-4 gene generates an antigenic peptide recognized by autologous cytolytic T lymphocytes on a human lung carcinoma. Cancer Res (2001) 61:4078–83.
67. Hogan KT, Eisinger DP, Cupp SB III, Lekstrom KJ, Deacon DD, Shabanowitz J, et al. The peptide recognized by HLA-A68.2-restricted, squamous cell carcinoma of the lung-specific cytotoxic T lymphocytes is derived from a mutated elongation factor 2 gene. Cancer Res (1998) 58:5144–50.
68. Karanikas V, Colau D, Baurain JF, Chiari R, Thonnard J, Gutierrez-Roelens I, et al. High frequency of cytolytic T lymphocytes directed against a tumor-specific mutated antigen detectable with HLA tetramers in the blood of a lung carcinoma patient with long survival. Cancer Res (2001) 61: 3718–24.
69. Clark RE, Dodi IA, Hill SC, Lill JR, Aubert G, Macintyre AR, et al. Direct evidence that leukemic cells present HLA-associated immunogenic peptides derived from the BCR-ABL b3a2 fusion protein. Blood (2001) 98:2887–93. doi:10.1182/blood.V98.10.2887
70. Sahin U, Tureci O, Schmitt H, Cochlovius B, Johannes T, Schmits R, et al. Human neoplasms elicit multiple specific immune responses in the autologous host. Proc Natl Acad Sci U S A (1995) 92:11810–3. doi:10.1073/pnas.92.25.11810
71. Scanlan MJ, Chen YT, Williamson B, Gure AO, Stockert E, Gordan JD, et al. Characterization of human colon cancer antigens recognized by autologous antibodies. Int J Cancer (1998) 76:652–8. doi:10.1002/(SICI)1097-0215(19980529)76:5<652::AID-IJC7>3.3.CO;2-9
72. Garrido F, Ruiz-Cabello F, Cabrera T, Perez-Villar JJ, Lopez-Botet M, Duggan-Keen M, et al. Implications for immunosurveillance of altered HLA class I phenotypes in human tumours. Immunol Today (1997) 18:89–95. doi:10.1016/S0167-5699(96)10075-X
73. D’Urso CM, Wang ZG, Cao Y, Tatake R, Zeff RA, Ferrone S. Lack of HLA class I antigen expression by cultured melanoma cells FO-1 due to a defect in B2m gene expression. J Clin Invest (1991) 87:284–92. doi:10.1172/JCI114984
74. Perez B, Benitez R, Fernandez MA, Oliva MR, Soto JL, Serrano S, et al. A new beta 2 microglobulin mutation found in a melanoma tumor cell line. Tissue Antigens (1999) 53:569–72. doi:10.1034/j.1399-0039.1999.530607.x
75. Jimenez P, Canton J, Collado A, Cabrera T, Serrano A, Real LM, et al. Chromosome loss is the most frequent mechanism contributing to HLA haplotype loss in human tumors. Int J Cancer (1999) 83:91–7. doi:10.1002/(SICI)1097-0215(19990924)83:1<91::AID-IJC17>3.0.CO;2-4
76. Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA, Golub TR, et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature (2014) 505:495–501. doi:10.1038/nature12912
77. Lippitz BE. Cytokine patterns in patients with cancer: a systematic review. Lancet Oncol (2013) 14:e218–28. doi:10.1016/S1470-2045(12)70582-X
78. Principe DR, Doll JA, Bauer J, Jung B, Munshi HG, Bartholin L, et al. TGF-beta: duality of function between tumor prevention and carcinogenesis. J Natl Cancer Inst (2014) 106:djt369. doi:10.1093/jnci/djt369
79. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol (2002) 3:991–8. doi:10.1038/ni1102-991
80. Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, et al. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science (1999) 285:727–9. doi:10.1126/science.285.5428.727
81. Groh V, Bahram S, Bauer S, Herman A, Beauchamp M, Spies T. Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proc Natl Acad Sci U S A (1996) 93:12445–50. doi:10.1073/pnas.93.22.12445
82. Raulet DH, Gasser S, Gowen BG, Deng W, Jung H. Regulation of ligands for the NKG2D activating receptor. Annu Rev Immunol (2013) 31:413–41. doi:10.1146/annurev-immunol-032712-095951
83. Shafi S, Vantourout P, Wallace G, Antoun A, Vaughan R, Stanford M, et al. An NKG2D-mediated human lymphoid stress surveillance response with high interindividual variation. Sci Transl Med (2011) 3:113ra124. doi:10.1126/scitranslmed.3002922
84. Gasser S, Orsulic S, Brown EJ, Raulet DH. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature (2005) 436:1186–90. doi:10.1038/nature03884
85. Boissel N, Rea D, Tieng V, Dulphy N, Brun M, Cayuela JM, et al. BCR/ABL oncogene directly controls MHC class I chain-related molecule A expression in chronic myelogenous leukemia. J Immunol (2006) 176:5108–16. doi:10.4049/jimmunol.176.8.5108
86. Liu XV, Ho SS, Tan JJ, Kamran N, Gasser S. Ras activation induces expression of Raet1 family NK receptor ligands. J Immunol (2012) 189:1826–34. doi:10.4049/jimmunol.1200965
87. Vantourout P, Willcox C, Turner A, Swanson CM, Haque Y, Sobolev O, et al. Immunological visibility: posttranscriptional regulation of human NKG2D ligands by the EGF receptor pathway. Sci Transl Med (2014) 6:231ra249. doi:10.1126/scitranslmed.3007579
88. Jung H, Hsiung B, Pestal K, Procyk E, Raulet DH. RAE-1 ligands for the NKG2D receptor are regulated by E2F transcription factors, which control cell cycle entry. J Exp Med (2012) 209:2409–22. doi:10.1084/jem.20120565
89. Groh V, Rhinehart R, Secrist H, Bauer S, Grabstein KH, Spies T. Broad tumor-associated expression and recognition by tumor-derived gamma delta T cells of MICA and MICB. Proc Natl Acad Sci U S A (1999) 96:6879–84. doi:10.1073/pnas.96.12.6879
90. Jinushi M, Takehara T, Tatsumi T, Kanto T, Groh V, Spies T, et al. Expression and role of MICA and MICB in human hepatocellular carcinomas and their regulation by retinoic acid. Int J Cancer (2003) 104:354–61. doi:10.1002/ijc.10966
91. Cerwenka A, Baron JL, Lanier LL. Ectopic expression of retinoic acid early inducible-1 gene (RAE-1) permits natural killer cell-mediated rejection of a MHC class I-bearing tumor in vivo. Proc Natl Acad Sci U S A (2001) 98:11521–6. doi:10.1073/pnas.201238598
92. Diefenbach A, Jensen ER, Jamieson AM, Raulet DH. RAE1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature (2001) 413:165–71. doi:10.1038/35093109
93. Smyth MJ, Swann J, Cretney E, Zerafa N, Yokoyama WM, Hayakawa Y. NKG2D function protects the host from tumor initiation. J Exp Med (2005) 202:583–8. doi:10.1084/jem.20050994
94. Guerra N, Tan YX, Joncker NT, Choy A, Gallardo F, Xiong N, et al. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity (2008) 28:571–80. doi:10.1016/j.immuni.2008.02.016
95. Chen D, Juko-Pecirep I, Hammer J, Ivansson E, Enroth S, Gustavsson I, et al. Genome-wide association study of susceptibility loci for cervical cancer. J Natl Cancer Inst (2013) 105:624–33. doi:10.1093/jnci/djt051
96. Melum E, Karlsen TH, Schrumpf E, Bergquist A, Thorsby E, Boberg KM, et al. Cholangiocarcinoma in primary sclerosing cholangitis is associated with NKG2D polymorphisms. Hepatology (2008) 47:90–6. doi:10.1002/hep.21964
97. Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science (2013) 342:1432–3. doi:10.1126/science.342.6165.1432
98. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med (2010) 363:711–23. doi:10.1056/NEJMoa1003466
99. Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med (2011) 364:2517–26. doi:10.1056/NEJMoa1104621
100. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med (2012) 366:2443–54. doi:10.1056/NEJMoa1200690
101. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med (2012) 366:2455–65. doi:10.1056/NEJMoa1200694
102. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med (2013) 369:122–33. doi:10.1056/NEJMoa1302369
Keywords: cancer immunosurveillance, primary immunodeficiency, cancer risk, organ transplantation, immunosuppressive drugs, HIV, NKG2D, checkpoint blockade
Citation: Corthay A (2014) Does the immune system naturally protect against cancer? Front. Immunol. 5:197. doi: 10.3389/fimmu.2014.00197
Received: 13 February 2014; Accepted: 22 April 2014;
Published online: 12 May 2014.
Edited by:
Fang-Ping Huang, Imperial College London, UKReviewed by:
Stephan Gasser, National University of Singapore, SingaporeSusanna Mandruzzato, Università degli Studi di Padova, Italy
Copyright: © 2014 Corthay. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Alexandre Corthay, Tumor Immunology Group, Department of Pathology, Oslo University Hospital Rikshospitalet, PO Box 4950, Nydalen, Oslo NO-0424, Norway e-mail: alexandre.corthay@ibv.uio.no