Vijay Kumar*†
John H. Stewart IV*- Department of Surgery, Laboratory of Tumor Immunology and Immunotherapy, Morehouse School of Medicine, Atlanta, GA, United States
Editorial on the Research Topic
Immunology of cachexia
Cachexia manifests as a chronic inflammatory condition with profound weight loss that includes muscle wasting/sarcopenia with or without loss of adipose/fat mass (1). It is more common in patients with chronic infections, such as acquired immunodeficiency syndrome (AIDS, a human immunodeficiency virus (HIV)-1 infection) and tuberculosis (caused by mycobacterium tuberculosis infection), chronic inflammatory diseases, and many aggressive cancers (gastrointestinal and lung cancers) (2–5). Cancer-associated cachexia (CAC) cannot be easily differentiated from anorexia or other causes of weight or muscle loss. Therefore, CAC is considered as a multifactorial syndrome characterized by ongoing skeletal muscle loss, with or without fat loss and can be partially but not entirely reversed by conventional nutrition support (6). CAC is responsible for 30% of all cancer deaths, although cachexia is not prevalent in all cancer types (7). Furthermore, CAC increases with cancer metastasis, which proves lethal to patients due to failed therapeutic breakthrough to reverse CAC and decreased efficacy of available immunotherapeutics and chemotherapeutics (7, 8). Furthermore, altered immune responses that support tumor growth and metastasis also play critical roles in the development of cachexia. These findings support further investigation (9, 10). Therefore, the current Research Topic entitled “Immunology of cachexia” is a step in this direction.
de Cassia Rosa de Jesus et al. discuss the heterogenous expression of the NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3) that forms inflammasomes upon activation and induces IL-1β and IL-18 secretion to create a pro-inflammatory environment in the adipose tissue (AT) of colorectal cancer (CC) patients. These patients have different comorbidities, including systemic arterial hypertension (seen most frequently). Their study has shown increased systemic inflammation (decreased circulating albumin and increased C-Reactive Protein (CRP) levels) in patients with CC who present with cachexia (defined as per the international consensus criteria) as compared to the control group (1). They further found NLRP3 overexpression in the subcutaneous adipose tissues (scAT) of patients with CC compared to control and weight-stable patients with CC (WSC). They observed similar findings in the visceral adipose tissue (VAT) close to the tumor (peritumoral adipose tissue, PtAT) of patients with CC who present with cachexia. The scAT of patients with CC-associated cachexia and WSC overexpress caspase-1 (CASP-1), a critical component of NLRP3 inflammasome relative to the control group. However, in vitro studies associated with lipopolysaccharide (LPS) stimulation in scAT and ptAT have variable results due to dysregulated TLR expression and function. Hence, further research in this area is warranted to establish the immunoregulatory role of NLRP3 inflammasomes in CAC. Furthermore, NLRP3 inflammasome activation plays a role in hypertension therefore further studies in different cells, including immune cells are critical to establish the role of NRLP3 inflammasome activation in CC cachexia without hypertension (11–13).
Sun et al. have shown that the Institute of Cancer Research (ICR) mice develop skeletal muscle loss/atrophy in response to continuous IL-6 infusions in their tibialis anterior muscles via immune receptor activation and metabolic energy reduction. For example, IL-6 infusion downregulates several genes involved in oxidative phosphorylation (OXPHOS) and tricarboxylic acid (TCA) or Krebs cycle and supports aerobic glycolysis to support pro-inflammatory immunometabolic reprograming (14, 15). Furthermore, glycolysis also supports NLRP3 inflammasome activation to aggravate the inflammation and skeletal muscle cell pyroptosis (16, 17). They have further shown that signal transducer and activator of transcription 3 (STAT3), NF-κB, tumor protein 53 (TP53 or p53), and myogenin (MyoG) signaling in response to IL-6 are critical for cachexia-associated muscle atrophy. Hence, IL-6 via glycolysis may activate NLRP3 inflammasome in skeletal muscle and fat cells of patients with cancer to induce cachexia.
Sun et al. have shown the differential expression of necroptosis-related genes (NRGs) in patients with CC and help to classify patients into high and low-risk groups. Furthermore, necroptosis mediates muscle protein degradation in a cachexia model and proteins that signal for necroptosis can activate NLRP3 inflammasome (18–20). Thus, NLRP3 inflammasome activation through different interconnected pro-inflammatory signaling events serves as a critical mediator of the CAC. Hence, future studies that delineate necroptosis and immune reprograming in CAC are needed. Furthermore, the study by Pinci et al. in the Research Topic has indicated that tumor necrosis factor (TNF), released by the activation of a disintegrin and metalloproteinase (ADAM proteases), serves as a necroptosis-associated alarmin. The increased TNF levels support cachexia by increasing the loss of AT and proteolysis and decreasing protein, lipid, and glycogen synthesis, along with its pro-inflammatory action (21). Therefore, TLR and NLRP3 activation-mediated pro-inflammatory events are critical players in the immunopathogenesis of cachexia and need further investigation.
Cunningham et al. investigated the platelet status in cancer cachexia progression by using ApcMin/+ mice. This study indicates that platelet numbers increase before cachexia development and can become activated during its progression. In the pre-cachexia stage, these mice showed elevated levels of transforming growth factor β2 (TGFβ2), TGFβ3, Mothers against decapentaplegic homolog 3 or SMAD family member 3 (SMAD3), and IL-1β overexpression in their skeletal muscles. The ApcMin/+ mice with severe cachexia overexpressed Ly6G, CD206 (mannose receptor), and IL-10 mRNA. The pre-cachectic ApcMin/+ mice show decreased physical activity and anemia that increases with the cachexia severity. Earlier clinical study has indicated a negative association between platelet count and one-year overall survival of patients with cancer cachexia (22). Furthermore, increased platelet count is associated with renal cachexia and cardiovascular mortality in end-stage renal disease patients (23). Hence, understanding the immunological functions of platelets in cachexia is important. For example, NLRP3 inflammasome activation in platelets is a critical pro-inflammatory event for multi-organ injury and platelets also regulate the NRLP3 inflammasome activation in other immune cells, such as macrophages and neutrophils by licensing The NLRP3 transcription (24, 25). Therefore, it will be interesting to observe the platelet mediated NLRP3 inflammasome regulation in myeloid immune cells (MICs), myocytes, and adipocytes of patients with CAC.
Minagawa et al. have shown that deleting the transformed follicular lymphoma (TFL) gene induces extraordinary C-X-C chemokine ligand 13 (CXCL13 or B cell-attracting chemokine 1or BCA-1) secretion and cachexia development in transgenic VavP-Bcl2 mice, thus causing early death. CXCL13 is a ligand for CXCR5 (Burkitt’s lymphoma receptor 1 or BLR1) and controls B cell development and trafficking (26, 27). Hence, this study indicates that CXCL13 overexpression and cachexia development in lymphoma occur downstream of TFL activity. Further studies will help to understand the immunological role of CXCL13 and TFL in other cancers and associated cachexia. Therefore, innate and adaptive immune components play a critical role in the immunology of CAC depending on the tumor type and stage, comprising a novel therapeutic approach for immunotherapeutic targeting.
Immune checkpoint inhibitors (ICIs) are the latest immunotherapies available to patients with cancer. The review by Li et al. discuss the advanced hepatocellular carcinoma (AHCC) tumor immune microenvironment (TIME) and role of PD-1/PD-L1 checkpoint inhibitors alone or in different combinations along with associated challenges. Furthermore, a clinical case report by Li et al. suggests the efficacy of S-1 and Oxaliplatin (SOX) chemotherapy with anti-PD-1 and invariant natural killer T (iNKT) cell immunotherapies in a patient with stage IV gastric adenocarcinoma with liver metastasis. Patients with Stage IV gastric adenocarcinoma with liver metastasis develop severe cachexia. Therefore, the cachexia index (CXI) can serve as a good prognostic marker in patients with gastric cancer (GC) and CC (28, 29) This is applicable to patients with low CXI, particularly those combined with cachexia, low body mass index (BMI) or advanced stage cancer (28, 29). Therefore, CXI has the potential to serve as a predictive marker for metastatic GC and efficacy of immunotherapeutic agents. Furthermore, Jia et al. in their clinical trial data, have indicated the efficacy of sintilimab in combination with autologous NK cells as a second-line treatment for patients with advanced non-small cell lung cancer (NSCLC). Cachexia is a negative prognostic indicator in patients receiving second line systemic chemotherapy (30). Therefore, it is important to observe the impact of autologous NK cell-based immunotherapy on cachexia in patients with advanced cancers and vice versa.
Cachexia influences the efficacy of ICIs, such as PD-1/PD-L1 inhibitors in advanced cancers. For example, cachexia in patients with advanced NSCLC reduces the efficacy of PD-1/PD-L1 checkpoint inhibitors (31, 32). Therefore, predicting the risk of cachexia development in advanced cancers, including advanced NSCLC and AHCC, before the starting ICIs has a potential to improve clinical outcomes (33, 34).
In the last article of the Research Topic, Robinson et al. have discussed the impact of inflammation and acute phase activation in cancer cachexia. For example, emerging studies indicate the presence of intact regulatory type 2 immunity (abundant IL-33 and eotaxin-2 level) in the visceral adipose tissue (VAT) of experimental and clinical cases of CC and pancreatic cancer-associate cachexia (35). Furthermore, local macrophages in the VAT are also critical for cachexia-induced fat loos in patients with cancer, including HCC (36). Therefore, cachexia, including CAC pathogenesis involves dysregulated immune response and suggests further research to understand the immunology of cachexia and designing novel immune-based biomarkers and therapeutics.
Author contributions
VK: Conceptualization, Writing – original draft, Writing – review & editing. JS: Writing – review & editing.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Evans WJ, Morley JE, Argilés J, Bales C, Baracos V, Guttridge D, et al. Cachexia: a new definition. Clin Nutr (2008) 27:793–9. doi: 10.1016/j.clnu.2008.06.013
2. Keithley JK, Swanson B. HIV-associated wasting. J Assoc Nurses AIDS Care (2013) 24(1 Suppl):S103–111. doi: 10.1016/j.jana.2012.06.013
3. Cheung WW, Paik KH, Mak RH. Inflammation and cachexia in chronic kidney disease. Pediatr Nephrol (2010) 25:711–24. doi: 10.1007/s00467-009-1427-z
4. Oliveira EA, Cheung WW, Toma KG, Mak RH. Muscle wasting in chronic kidney disease. Pediatr Nephrol (2018) 33:789–98. doi: 10.1007/s00467-017-3684-6
5. Baracos VE, Martin L, Korc M, Guttridge DC, Fearon KCH. Cancer-associated cachexia. Nat Rev Dis Primers (2018) 4:17105. doi: 10.1038/nrdp.2017.105
6. Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol (2011) 12:489–95. doi: 10.1016/S1470-2045(10)70218-7
7. Siff T, Parajuli P, Razzaque MS, Atfi A. Cancer-mediated muscle cachexia: etiology and clinical management. Trends Endocrinol Metab (2021) 32:382–402. doi: 10.1016/j.tem.2021.03.007
8. Biswas AK, Acharyya S. Understanding cachexia in the context of metastatic progression. Nat Rev Cancer (2020) 20:274–84. doi: 10.1038/s41568-020-0251-4
9. Argilés JM, López-Soriano FJ, Stemmler B, Busquets S. Cancer-associated cachexia — understanding the tumour macroenvironment and microenvironment to improve management. Nat Rev Clin Oncol (2023) 20:250–64. doi: 10.1038/s41571-023-00734-5
10. Wu Q, Liu Z, Li B, Liu Y-e, Wang P. Immunoregulation in cancer-associated cachexia. J Adv Res (2023) S2090-1232(23):00124–128. doi: 10.1016/j.jare.2023.04.018
11. Bartoli-Leonard F, Zimmer J, Sonawane AR, Perez K, Turner ME, Kuraoka S, et al. NLRP3 inflammasome activation in peripheral arterial disease. J Am Heart Assoc (2023) 12:e026945. doi: 10.1161/JAHA.122.026945
12. Pasqua T, Pagliaro P, Rocca C, Angelone T, Penna C. Role of NLRP-3 inflammasome in hypertension: A potential therapeutic target. Curr Pharm Biotechnol (2018) 19:708–14. doi: 10.2174/1389201019666180808162011
13. Krishnan SM, Ling YH, Huuskes BM, Ferens DM, Saini N, Chan CT, et al. Pharmacological inhibition of the NLRP3 inflammasome reduces blood pressure, renal damage, and dysfunction in salt-sensitive hypertension. Cardiovasc Res (2018) 115:776–87. doi: 10.1093/cvr/cvy252
14. Ando M, Uehara I, Kogure K, Asano Y, Nakajima W, Abe Y, et al. Interleukin 6 enhances glycolysis through expression of the glycolytic enzymes hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3. J Nippon Med Sch (2010) 77:97–105. doi: 10.1272/jnms.77.97
15. Han J, Meng Q, Xi Q, Zhang Y, Zhuang Q, Han Y, et al. Interleukin-6 stimulates aerobic glycolysis by regulating PFKFB3 at early stage of colorectal cancer. Int J Oncol (2016) 48:215–24. doi: 10.3892/ijo.2015.3225
16. Liu D, Xiao Y, Zhou B, Gao S, Li L, Zhao L, et al. PKM2-dependent glycolysis promotes skeletal muscle cell pyroptosis by activating the NLRP3 inflammasome in dermatomyositis/polymyositis. Rheumatol (Oxford) (2021) 60:2177–89. doi: 10.1093/rheumatology/keaa473
17. Xie M, Yu Y, Kang R, Zhu S, Yang L, Zeng L, et al. PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation. Nat Commun (2016) 7:13280. doi: 10.1038/ncomms13280
18. Guo J, Qin X, Wang Y, Li X, Wang X, Zhu H, et al. Necroptosis mediates muscle protein degradation in a cachexia model of weanling pig with lipopolysaccharide challenge. Int J Mol Sci (2023) 24(13):10923. doi: 10.3390/ijms241310923
19. Kang TB, Yang SH, Toth B, Kovalenko A, Wallach D. Activation of the NLRP3 inflammasome by proteins that signal for necroptosis. Methods Enzymol (2014) 545:67–81. doi: 10.1016/B978-0-12-801430-1.00003-2
20. Conos SA, Chen KW, De Nardo D, Hara H, Whitehead L, Núñez G, et al. Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner. Proc Natl Acad Sci (2017) 114:E961–9. doi: 10.1073/pnas.1613305114
21. Patel HJ, Patel BM. TNF-α and cancer cachexia: Molecular insights and clinical implications. Life Sci (2017) 170:56–63. doi: 10.1016/j.lfs.2016.11.033
22. Liu Y, Ge Y, Li Q, Ruan G, Zhang Q, Zhang X, et al. Association between platelet count with 1-year survival in patients with cancer cachexia. J Cancer (2021) 12:7436–44. doi: 10.7150/jca.62788
23. Molnar MZ, Streja E, Kovesdy CP, Budoff MJ, Nissenson AR, Krishnan M, et al. High platelet count as a link between renal cachexia and cardiovascular mortality in end-stage renal disease patients. Am J Clin Nutr (2011) 94:945–54. doi: 10.3945/ajcn.111.014639
24. Rolfes V, Ribeiro LS, Hawwari I, Böttcher L, Rosero N, Maasewerd S, et al. Platelets fuel the inflammasome activation of innate immune cells. Cell Rep (2020) 31:107615. doi: 10.1016/j.celrep.2020.107615
25. Cornelius DC, Baik CH, Travis OK, White DL, Young CM, Austin Pierce W, et al. NLRP3 inflammasome activation in platelets in response to sepsis. Physiol Rep (2019) 7:e14073. doi: 10.14814/phy2.14073
26. Kaiser E, Förster R, Wolf I, Ebensperger C, Kuehl WM, Lipp M. The G protein-coupled receptor BLR1 is involved in murine B cell differentiation and is also expressed in neuronal tissues. Eur J Immunol (1993) 23:2532–9. doi: 10.1002/eji.1830231023
27. Legler DF, Loetscher M, Roos RS, Clark-Lewis I, Baggiolini M, Moser B. B cell-attracting chemokine 1, a human CXC chemokine expressed in lymphoid tissues, selectively attracts B lymphocytes via BLR1/CXCR5. J Exp Med (1998) 187:655–60. doi: 10.1084/jem.187.4.655
28. Gong C, Wan Q, Zhao R, Zuo X, Chen Y, Li T. Cachexia index as a prognostic indicator in patients with gastric cancer: A retrospective study. Cancers (Basel) (2022) 14(18):4400. doi: 10.3390/cancers14184400
29. Wan Q, Yuan Q, Zhao R, Shen X, Chen Y, Li T, et al. Prognostic value of cachexia index in patients with colorectal cancer: A retrospective study. Front Oncol (2022) 12:984459. doi: 10.3389/fonc.2022.984459
30. Kimura M, Naito T, Kenmotsu H, Taira T, Wakuda K, Oyakawa T, et al. Prognostic impact of cancer cachexia in patients with advanced non-small cell lung cancer. Support Care Cancer (2015) 23:1699–708. doi: 10.1007/s00520-014-2534-3
31. Miyawaki T, Naito T, Kodama A, Nishioka N, Miyawaki E, Mamesaya N, et al. Desensitizing effect of cancer cachexia on immune checkpoint inhibitors in patients with advanced NSCLC. JTO Clin Res Rep (2020) 1:100020. doi: 10.1016/j.jtocrr.2020.100020
32. Roch B, Coffy A, Jean-Baptiste S, Palaysi E, Daures J-P, Pujol J-L, et al. Cachexia - sarcopenia as a determinant of disease control rate and survival in non-small lung cancer patients receiving immune-checkpoint inhibitors. Lung Cancer (2020) 143:19–26. doi: 10.1016/j.lungcan.2020.03.003
33. Mu W, Katsoulakis E, Whelan CJ, Gage KL, Schabath MB, Gillies RJ. Radiomics predicts risk of cachexia in advanced NSCLC patients treated with immune checkpoint inhibitors. Br J Cancer (2021) 125:229–39. doi: 10.1038/s41416-021-01375-0
34. Goh MJ, Kang W, Jeong WK, Sinn DH, Gwak GY, Paik YH, et al. Prognostic significance of cachexia index in patients with advanced hepatocellular carcinoma treated with systemic chemotherapy. Sci Rep (2022) 12:7647. doi: 10.1038/s41598-022-11736-1
35. Lenehan PJ, Cirella A, Uchida AM, Crowley SJ, Sharova T, Boland G, et al. Type 2 immunity is maintained during cancer-associated adipose tissue wasting. Immunother Adv (2021) 1:ltab011. doi: 10.1093/immadv/ltab011
Keywords: cachexia, immunity, inflammation, NLRP3 inflammasome, cancer, immune-checkpoint inhibitors
Citation: Kumar V and Stewart JH IV (2023) Editorial: Immunology of cachexia. Front. Immunol. 14:1339263. doi: 10.3389/fimmu.2023.1339263
Received: 15 November 2023; Accepted: 28 November 2023;
Published: 05 December 2023.
Edited and Reviewed by:
Giamila Fantuzzi, University of Illinois Chicago, United StatesCopyright © 2023 Kumar and Stewart. 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) and the copyright owner(s) 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: John H. Stewart IV, jstewart@msm.edu; Vijay Kumar, vijkumar@msm.edu; vij_tox@yahoo.com
†ORCID: Vijay Kumar, orcid.org/0000-0001-9741-3597