Immune Checkpoint Inhibition and Radiotherapy in Head and Neck Squamous Cell Carcinoma: Synergisms and Resistance Mechanisms

AbstractImmune checkpoint inhibition has emerged as an integral part of the standard-of-care for head and neck squamous cell carcinoma (HNSCC) in recurrent and/or metastatic stages. Clinical responses are impressive but remain limited to a minority of patients. Primary resistance of never-responders is considered to derive from host- and tumor-specific characteristics, the latter comprising tumor immune checkpoint activity, immune contexture, tumor mutational burden, neo-antigen load, and others. Secondary resistance of initially responding patients in addition, appears to be driven predominantly by irreversible T-cell exhaustion and therapy-induced selection of tumor cell clones with mutations in critical genes involved in the response to immune checkpoint inhibition. With particular focus on primary resistance against immune checkpoint inhibition, scientific interest of preclinical and clinical researchers currently aims at the development and evaluation of combined modality treatment approaches. Radiotherapy is a highly promising partner in this regard and represents a crucial treatment modality for patients with locally advanced HNSCC. Historically established as cytotoxic anti-cancer treatment, a growing body of evidence has shown additional locoregional and systemic immunomodulatory effects of radiotherapy. These are largely attributed to reprogramming of the tumor microenvironment driven by dying and senescent irradiated tumor and normal tissue cells and the concomitant cascade of danger signals, chemokines, and cytokines which stimulate immune cell recruitment and activation. Moreover, the irradiated state of tumor cells bears interesting analogy to the anti-viral state, since fragments of nuclear and mitochondrial DNA that are released into the cytosol can stimulate cytosolic nucleic acid sensors to produce intra-tumoral type I interferons which are essential to (re-)activate the cancer immunity cycle and (re-)invigorate systemic anti-tumor T-cell responses. Apart from these tumor adjuvanticity enhancing effects, several reports have also described increased tumor antigenicity upon radiotherapy originating from radiation-induced exposure of neo-antigens. Collectively, radiotherapy thus may serve as a means of personalized in situ vaccination which can synergize with immune checkpoint inhibition and may help to undermine primary resistance. First clinical experiences have shown that scheduling and dosing of such combined modality treatment regimens are challenging. Moreover, recent preclinical evidence suggests that particularly the role of radiation-induced cytokines and interferons appears to be complex in such combined modality settings due to their ambiguous effects on tumor and immune cells in the tumor microenvironment. The signaling cascades that orchestrate immune cell (re-)activation and cell fate decisions in irradiated tumor cells, including tumor cell survival, proliferation, and/or metastasis formation, are intimately interconnected and require further in-depth investigation.