Radiotherapy: Changing the Game in Immunotherapy

Abstract

Immune checkpoint inhibitors are effective in cancer treatment. A pre-existing immune response demonstrated by significant pretreatment tumor lymphocytic infiltration is a pre-requisite for response. Within such infiltrated tumors, referred as "hot", immune checkpoint inhibitors rescue anti-tumor T cells activity. In contrast, "cold" tumors lack lymphocytic infiltration and are refractory to immunotherapy. Preclinical data show that radiotherapy sensitizes refractory tumors to immune checkpoint inhibitors by recruiting anti-tumor T cells. Despite the growing number of clinical studies testing radiation's ability 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 immunotherapy's effects but a "game changer", and propose a blueprint to test this.

Key Figure 1. Converting “cold” tumors into “hot” ones

Lack of T cell infiltration may be due to absence of dendritic cells (DCs) or presence of DCs that are not activated (tolerogenic DCs) (a). In this situation, anti-tumor T cells are not generated. In other cases, anti-tumor T cells that are generated spontaneously or by vaccination are excluded from the tumor by the vascular barrier, which is induced by M2 tumor-associated macrophages (TAMs) (b). By inducing cancer cell death coupled with release of danger signals, radiation can promote DC activation and their migration to the tumor-draining lymph nodes (TDLN) where they activate tumor-specific T cells. Activated effector T cells then migrate to the tumor, kill cancer cells and secrete cytokines that further activate DCs and promote TAM polarization to anti-tumor M1 phenotype, converting the tumor from cold to hot (c). Low doses of radiation can also reprogram TAM towards the M1 phenotype, allowing pre-existing T cells to infiltrate the tumor.