Immunogenic effects of chemotherapy-induced tumor cell death

Abstract

Emerging evidence suggests that the clinical success of conventional chemotherapy is not solely attributed to tumor cell toxicity, but also results from the restoration of immunosurveillance, which has been largely neglected in the past preclinical and clinical research. Antitumor immune response can be primed by immunogenic cell death (ICD), a type of cell death characterized by cell-surface translocation of calreticulin (CRT), extracellular release of ATP and high mobility group box 1 (HMGB1), and stimulation of type I interferon (IFN) responses. Here we summarize recent studies showing conventional chemotherapeutics as ICD inducers, which are capable of modulating tumor infiltrating lymphocytes (TILs) and reactivating antitumor immunity within an immuno-suppressive microenvironment. Such immunological effects of conventional chemotherapy are likely critical for better prognosis of cancer patients. Furthermore, combination of ICD-inducing chemotherapeutics with immunotherapy is a promising approach for improving the clinical outcomes of cancer patients.

Keywords: Antitumor immunity; Autophagy; Conventional chemotherapy; ER stress; Immunogenic cell death; Immunosurveillance.

Figure 1

Mechanism of immunogenic cell death (ICD). In response to ICD-inducing chemotherapeutics, tumor cells expose CRT on their surface at a pre-apoptotic stage, secrete ATP during apoptosis, and release HMGB1 during secondary necrosis. These damage-associated molecular pattern (DAMP) molecules liberated from dying tumor cells stimulate the recruitment of DCs into the tumor bed, the uptake and processing of tumor antigens, and the optimal antigen presentation to T cells. However, the binding of cell-surface CD47 to SIRP$\alpha$ on DCs inhibits their phagocytic function. Phagocytosis of tumor cells requires both the activation of pro-phagocytic signals as well as simultaneous disruption of the anti-phagocytic signal CD47. Cross-priming of CD8+ CTLs is triggered by mature DCs and γδ T cells in an IL-1β- and IL-17-dependent manner. Primed CTLs elicit direct cytotoxic response and kill remaining tumor cells through the generation of IFN-γ, perforin-1 and granzyme B.