Role of Local Radiation Therapy in Cancer Immunotherapy

Abstract

The recent success of cancer immunotherapy has demonstrated the power of the immune system to clear tumors, generating renewed enthusiasm for identifying ways to induce antitumor immune responses in patients. Natural antitumor immune responses are detectable in a fraction of patients across multiple malignant neoplasms and can be reactivated by targeting rate-limiting immunosuppressive mechanisms. In most patients, however, interventions to induce a de novo antitumor immune response are necessary. We review growing evidence that radiation therapy targeted to the tumor can convert it into an in situ tumor vaccine by inducing release of antigens during cancer cell death in association with proinflammatory signals that trigger the innate immune system to activate tumor-specific T cells. In addition, radiation's effects on the tumor microenvironment enhance infiltration of activated T cells and can overcome some of the barriers to tumor rejection. Thus, the complementary effects of radiation on priming and effector phases of antitumor immunity make it an appealing strategy to generate immunity against a patient's own individual tumor, that through immunological memory, can result in long-lasting systemic responses. Several anecdotal cases have demonstrated the efficacy of combining radiation with available immunotherapies, and results of prospective trials are forthcoming.

The Positive Relationship Between γH2AX and PD-L1 Expression in Lung Squamous Cell Carcinoma

“…The APCs activate cytotoxic T cells, which in turn activate PD-L1 on the tumor cells, so inhibitors of immune checkpoint molecules are effective in tumors with a high mutation burden but not in those with driver mutations, such as EGFR and ALK. Our results may also support the notion of combining anti-PD-1 therapy with other cytotoxic therapies, such as alkylating agents and irradiation (20), which cause DNA double-strand breaks, possibly resulting in the expression of PD-L1 on the tumor cell surface. Recent studies have shown that the STING pathway is essential to the innate immune response against tumors.…”

Sequential Tracking of PD-L1 Expression and RAD50 Induction in Circulating Tumor and Stromal Cells of Lung Cancer Patients Undergoing Radiotherapy

“…Following double-stranded breaks in DNA, the RAD50/NBS/MRE11 complex rapidly translocates to the sites of the breakage, forming aggregated nuclear foci until the break is repaired, for example, IRIF (18,20,23,25). Thus, RAD50 can be used as a specific identifier of cells that have been exposed to high levels of radiation, acting as a biological tag of cells from patients that have been directly exposed to radiation targeted to a tumor mass (18)(19)(20)(21)(22)(23)(24)(26)(27)(28).…”

Radiation therapy and the abscopal effect: a concept comes of age

“…The recent successes of several immune check point inhibitor clinical trials in various malignancies have demonstrated wide applicability and enormous therapeutic potential of immunomodulation and have galvanized keen interest in this field (6)(7)(8)(9)(10). An ambitious goal of combining radiotherapy and immunotherapy in the clinic would be long term remission for cancer patients with metastatic disease, perhaps through an approach analogous to delivering an in-situ anti-tumor vaccine (11)(12)(13).…”