Combinatorial Approaches to Enhance Anti-Tumor Immunity: focus on Immune checkpoint blockade therapy

In recent decades, there has been substantial growth in our understanding of the immune system and its role in tumor growth and overall survival. A central finding has been the cross-talk between tumor cells and the surrounding environment or stroma. This tumor stroma, comprised of various cells, and extracellular matrix (ECM), has been shown to aid in suppressing host immune responses against tumor cells. Through immunosuppressive cytokine secretion, metabolic alterations, and other mechanisms, the tumor stroma provides a complex network of safeguards for tumor proliferation. With recent advances in more effective, localized treatment, radiation therapy (XRT) has allowed for strategies that can effectively alter and ablate tumor stromal tissue. This includes promoting immunogenic cell death through tumor antigen release to increasing immune cell trafficking, XRT has a unique advantage against the tumoral immune evasion mechanisms that are orchestrated by stromal cells. Current studies are underway to elucidate pathways within the tumor stroma as potential targets for immunotherapy and chemoradiation. This review summarizes the effects of tumor stroma in tumor immune evasion, explains how XRT may help overcome these effects, with potential combinatorial approaches for future treatment modalities.

Radiotherapy has been used for the treatment of cancer for over a century. Throughout this period, the therapeutic benefit of radiotherapy has continuously progressed due to technical developments and increased insight in the biological mechanisms underlying the cellular responses to irradiation. In order to further improve radiotherapy efficacy, there is a mounting interest in combining radiotherapy with other forms of therapy such as anti-angiogenic therapy or immunotherapy. These strategies provide different opportunities and challenges, especially with regard to dose scheduling and timing. Addressing these issues requires insight in the interaction between the different treatment modalities. In the current review, we describe the basic principles of the effects of radiotherapy on tumor vascularization and tumor immunity and vice versa. We discuss the main strategies to combine these treatment modalities and the hurdles that have to be overcome in order to maximize therapeutic effectivity. Finally, we evaluate the outstanding questions and present future prospects of a therapeutic triad for cancer.

Antibody-cytokine fusion proteins (immunocytokine) exert a potent anti-cancer effect; indeed, they target the immunosuppressive tumor microenvironment (TME) due to a specific anti-tumor antibody linked to immune activating cytokines. Once bound to the target tumor, the interleukin-2 (IL-2) immunocytokines composed of either full antibody or single chain Fv conjugated to IL-2 can promote the in situ recruitment and activation of natural killer (NK) cells and cytotoxic CD8⁺ T lymphocytes (CTL). This recruitment induces a TME switch toward a classical T helper 1 (Th1) anti-tumor immune response, supported by the cross-talk between NK and dendritic cells (DC). Furthermore, some IL-2 immunocytokines have been largely shown to trigger tumor cell killing by antibody dependent cellular cytotoxicity (ADCC), through Fcγ receptors engagement. The modulation of the TME can be also achieved with immunocytokines conjugated with a mutated form of IL-2 that impairs regulatory T (Treg) cell proliferation and activity. Preclinical animal models and more recently phase I/II clinical trials have shown that IL-2 immunocytokines can avoid the severe toxicities of the systemic administration of high doses of soluble IL-2 maintaining the potent anti-tumor effect of this cytokine. Also, very promising results have been reported using IL-2 immunocytokines delivered in combination with other immunocytokines, chemo-, radio-, anti-angiogenic therapies, and blockade of immune checkpoints. Here, we summarize and discuss the most relevant reported studies with a focus on: (a) the effects of IL-2 immunocytokines on innate and adaptive anti-tumor immune cell responses as well as immunosuppressive Treg cells and (b) the approaches to circumvent IL-2-mediated severe toxic side effects.