Dying of Stress: Chemotherapy, Radiotherapy, and Small-Molecule Inhibitors in Immunogenic Cell Death and Immunogenic Modulation

Abstract

Innovative strategies to re-establish the immune-mediated destruction of malignant cells is paramount to the success of anti-cancer therapy. Accumulating evidence suggests that radiotherapy and select chemotherapeutic drugs and small molecule inhibitors induce immunogenic cell stress on tumors that results in improved immune recognition and targeting of the malignant cells. Through immunogenic cell death, which entails the release of antigens and danger signals, and immunogenic modulation, wherein the phenotype of stressed cells is altered to become more susceptible to immune attack, radiotherapies, chemotherapies, and small-molecule inhibitors exert immune-mediated anti-tumor responses. In this review, we discuss the mechanisms of immunogenic cell death and immunogenic modulation and their relevance in the anti-tumor activity of radiotherapies, chemotherapies, and small-molecule inhibitors. Our aim is to feature the immunological aspects of conventional and targeted cancer therapies and highlight how these therapies may be compatible with emerging immunotherapy approaches.

Keywords: chemotherapy; combination therapy; immunogenic cell death; immunogenic cell stress; immunogenic modulation; immunotherapy; radiotherapy; small molecule inhibitor.

Figure 1

Radiotherapy, chemotherapy, and small-molecule inhibitors induce immunogenic cell stress resulting in immunological responses spanning from immune modulation to immunogenic cell death. Radiotherapy, select chemotherapy, and small-molecule inhibitors can induce immunogenic cell death, which is characterized by the release of DAMPs that promote antigen presenting cells to phagocytose the dying cells, process tumor antigens, and present tumor antigens to T cells. Tumor cells that were not eradicated by radiotherapy, chemotherapy, or small-molecule inhibitors undergo immunogenic modulation wherein the tumor phenotype is altered such that the malignant cells become more sensitized to T cell targeting. Combining radiotherapy, chemotherapy, and small-molecule inhibitors with immunotherapies that can engage, enhance, and enable effector T cells may result in improved immune-mediated eradication of neoplastic cells. DAMP: damage-associated molecular patterns; TAA: tumor-associated antigen; HMGB1: high-mobility group box 1; ATP: adenosine triphosphate; IFN: interferon; MHC: major histocompatibility complex; TCR: T-cell receptor.

Figure 2

Sublethal exposure to photon, proton, or alpha radiation increases CTL lysis of prostate carcinoma cells in vitro. (A) Sublethal exposure of LNCaP prostate tumor cells in vitro to photon, proton radiation, or alpha radiation (223Ra) has minimal effect on cell viability. Human prostate carcinoma cells were mock-irradiated (0 Gy) or treated with either 8 Gy of photon radiation, 8 Gy proton radiation, or 8 Gy of 223Ra. Radiation-treated cells were cultured for an additional 72–96 h, and viability was determined by AO/PI viability dye. Depicted is % viable cells. (B) Human LNCaP prostate carcinoma cells were mock-irradiated (0 Gy, open bars) or treated with either 8 Gy of photon radiation (closed bars), 8 Gy proton radiation (closed bars), 4 Gy of of 223Ra (gray bars), or 10 Gy of 223Ra (closed bars). Radiation treated cells were cultured for an additional 72–96 h and then used as targets in an overnight CTL lysis assay. CEA-, MUC-1-, and brachyury-specific CD8+ T cells were used as effectors at an E:T ratio of 30:1. Experiments were repeated 1–3 times with similar results. * = p < 0.05. Adapted from [132,140,141].