Radiotherapy: Changing the Game in Immunotherapy

Immunotherapy has revolutionized cancer treatment by demonstrating that blocking immunosuppressive pathways elicits remarkable and often durable responses in patients with metastatic disease. In most patients, blocking immunosuppression is ineffective without a treatment that induces de novo antitumor immune responses. Evidence that T cells recognize unique mutation-generated neoantigens in patients responding to immunotherapy implies that a tumor vaccine needs to be highly personalized. Emerging data that radiotherapy can convert the patient's own tumor into an in situ vaccine have resulted in significant interest for testing radiation in combination with immunotherapy. Successful personalized immunization of patients with cancer with local tumor irradiation could provide a simple, widely available, and cost-effective means to enhance responses to immunotherapy. Immune checkpoint inhibitors (ICI) are effective in cancer treatment. A pre-existing immune response demonstrated by significant pretreatment tumor lymphocytic infiltration is a prerequisite for response. Within such infiltrated tumors, referred to as ‘hot’ tumors, ICI rescue the activity of antitumor T cells. By contrast, ‘cold’ tumors lack lymphocytic infiltration and are refractory to immunotherapy. Preclinical data show that radiotherapy sensitizes refractory tumors to ICI by recruiting antitumor T cells. Despite the growing number of clinical studies testing the ability of radiation to enhance immunotherapy, clinical evidence that it converts cold tumors into responsive ones remains elusive. Here, we review evidence that radiotherapy is not only an occasional enhancer of the effects of immunotherapy, but also a ‘game changer’, and propose a blueprint to test this. Immune checkpoint inhibitors (ICI) are effective in cancer treatment. A pre-existing immune response demonstrated by significant pretreatment tumor lymphocytic infiltration is a prerequisite for response. Within such infiltrated tumors, referred to as ‘hot’ tumors, ICI rescue the activity of antitumor T cells. By contrast, ‘cold’ tumors lack lymphocytic infiltration and are refractory to immunotherapy. Preclinical data show that radiotherapy sensitizes refractory tumors to ICI by recruiting antitumor T cells. Despite the growing number of clinical studies testing the ability of radiation to enhance immunotherapy, clinical evidence that it converts cold tumors into responsive ones remains elusive. Here, we review evidence that radiotherapy is not only an occasional enhancer of the effects of immunotherapy, but also a ‘game changer’, and propose a blueprint to test this. from the Latin ab scopus; refers to tumor regression seen outside of the field of radiation. a receptor expressed by T cells that negatively regulates their ability to respond to antigen and proliferate. the most powerful antigen-presenting cells in the body, capable of activating naïve T cells. DCs uptake antigens from dying cells and can process and present them to T cells. a transcription factor that is induced by a decrease in available oxygen and regulates the expression of hundreds of genes, many of them cell type specific. refers to antibody-blocking receptors that are expressed on T cells and function as negative regulators of T cell activation and function. CTLA-4 and PD-1 are immune checkpoints. a receptor expressed on activated and exhausted T cells. Engagement of PD-1 by its ligands, PDL-1 or PDL-2, which are expressed on antigen-presenting cells, decreases T cell activation. PD-1 engagement by PDL-1 expressed on target cells (such as cancer cells) inhibits the function of effector T cells and can induce them to undergo apoptosis. energy deposited by ionizing radiation per unit mass, measured in gray (Gy): 1 Gy = 1 J/kg. a pathway that functions to detect the presence of cytosolic DNA and, in response, triggers expression of interferon type I and other inflammatory genes. molecular complex expressed on the surface of T cells and responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex molecules. a pleiotropic cytokine with multiple functions in development, tissue homeostasis, and inflammation. In the tumor, it promotes escape from immune control by inhibition of DC activation and effector differentiation of T cells. the non-neoplastic cellular environment of a tumor, including blood vessels, immune cells, fibroblasts, extracellular matrix, cytokines, chemokines, and other active compounds.