Harnessing the abscopal effect for gastrointestinal malignancies in the era of immunotherapy

Abstract

Gastrointestinal (GI) cancers are among the leading causes of cancer-related mortality and have traditionally been treated using a combination of surgical resection and chemoradiotherapy (CRT). While the introduction of immunotherapies over the last decade have dramatically changed the treatment landscape for some GI malignancies, including esophageal, gastric, and colorectal cancer, treatment resistance remains a major unaddressed obstacle for many patients. There has thus been emerging interest in determining the optimal treatment strategy for the delivery of immunotherapy in combination with traditional therapies. In this regard, a growing number of preclinical and clinical studies have suggested that combining radiation therapy (RT) with immunotherapy may work synergistically to improve treatment response through amplification of the abscopal effect. In this review, we discuss the rationale for RT in combination with immunotherapy. We further discuss how this knowledge may lead to a paradigm shift in the application of RT and highlight remaining issues pertaining to the delivery of combination therapy.

Keywords: Immunotherapy; abscopal effect; gastric cancer; gastrointestinal cancer; immune checkpoint inhibitor; radiation therapy; radiotherapy.

Figure 1

Schematic overview illustrating the mechanisms of synergy between radiotherapy and immunotherapy. Radiation therapy induces immunomodulatory effects that can boost anti-tumor immunity in several ways. Damage and death of cancer cells by radiation causes the release of tumor associated antigens, increased calreticulin, DAMPS which activate dendritic cells which prime CD8⁺ cytotoxic T cells. The activation of the cGAS-STING Pathway further leads to increase in pro-inflammatory cytokines, especially type I interferons which help to recruit active immune cells to the tumor microenvironment. The addition of immune checkpoint inhibitors such as anti-CTLA4 and anti-PD1/PD-L1 based therapies work synergistically with radiation therapy to promote an effective anti-tumor response. An anti-tumor immune response seen at a distant non-irradiated site through the abscopal effect may be one such benefit of combining immunotherapy with radiation (Elements of diagram created with Biorender.com). GI, gastrointestinal; DAMPs, damage associated molecular patterns; cGAS-STING, cyclic GMP-AMP synthase-stimulator of interferon genes; CTLA4, cytotoxic T lymphocyte-associated antigen 4; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1.