Abstract
Cytotoxic chemotherapeutics (CCTs) are widely used in the treatment of cancer. Although their mechanisms of action have been best understood in terms of targeting the apparatus of mitosis, an ability to stimulate anti-tumor immune responses is increasing the recognition of these agents as immunotherapies. Immune checkpoint blockade antibodies neutralize important, but specific, immune-regulatory interactions such as PD-1/PD-L1 and CTLA-4 to improve the anti-tumor immune response. However, CCTs can provide a broad-acting immune-stimulus against cancer, promoting both T-cell priming and recruitment to the tumor, which compliments the effects of immune checkpoint blockade. A key pathway in this process is “immunogenic cell death” (ICD) which occurs as a result of tumor cell endoplasmic reticulum stress and apoptosis elicited by CCTs. ICD involves a series of non-redundant signaling events which break tolerance and license anti-tumor antigen-specific T-cells, allowing CCTs to act as “in situ” tumor vaccination tools. Not all responses are tumor cell-intrinsic, as CCTs can also modulate the broader tumor microenvironment. This modulation occurs through preferential depletion of stromal cells which suppress and neutralize robust anti-tumor immune responses, such as myeloid cell populations and Tregs, while effector CD8+ and CD4+ T-cells and NK cells are relatively spared. The immune-stimulating effects of CCTs are dependent on chemotherapy class, dose and tumor cell sensitivity to the agent, highlighting the need to understand the underlying biology of these responses. This mini review considers the immune-stimulating effects of CCTs from a molecular perspective, specifically highlighting considerations for their utilization in the context of combinations with immunotherapy.
Highlights
Chemotherapy has been utilized for the treatment of cancer for over 70 years [1], and cytotoxic chemotherapeutics (CCTs) form part of the treatment regimen for many patients with cancer
There remains a majority of patients who are refractory to the current therapies or acquire resistance [12, 13], and there is a notable variation in patient responses to Immune checkpoint inhibitors (ICIs) across different tumor types [14, 15]
There is evidence that the IFN-γ expression by the CD8+ tumor infiltrating lymphocytes (TILs) is vital to the anti-tumor response elicited through immunogenic cell death” (ICD), as the immunological control of tumor growth by oxaliplatin has been demonstrated to be independent of perforin, and IFN-γdependent [32]
Summary
Chemotherapy has been utilized for the treatment of cancer for over 70 years [1], and cytotoxic chemotherapeutics (CCTs) form part of the treatment regimen for many patients with cancer. As single agents or as chemotherapy combinations, they rarely represent cures for advanced-stage disease [2], and the efficacy requires improvement in adjuvant and radiotherapy-combination settings
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