Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

Abstract

Conventional anticancer chemotherapy has been historically thought to act through direct killing of tumor cells. This concept stems from the fact that cytotoxic drugs interfere with DNA synthesis and replication. Accumulating evidence, however, indicates that the antitumor activities of chemotherapy also rely on several off-target effects, especially directed to the host immune system, that cooperate for successful tumor eradication. Chemotherapeutic agents stimulate both the innate and adaptive arms of the immune system through several modalities: (i) by promoting specific rearrangements on dying tumor cells, which render them visible to the immune system; (ii) by influencing the homeostasis of the hematopoietic compartment through transient lymphodepletion followed by rebound replenishment of immune cell pools; (iii) by subverting tumor-induced immunosuppressive mechanisms and (iv) by exerting direct or indirect stimulatory effects on immune effectors. Among the indirect ways of immune cell stimulation, some cytotoxic drugs have been shown to induce an immunogenic type of cell death in tumor cells, resulting in the emission of specific signals that trigger phagocytosis of cell debris and promote the maturation of dendritic cells, ultimately resulting in the induction of potent antitumor responses. Here, we provide an extensive overview of the multiple immune-based mechanisms exploited by the most commonly employed cytotoxic drugs, with the final aim of identifying prerequisites for optimal combination with immunotherapy strategies for the development of more effective treatments against cancer.

Figures

Figure 1

Immunomodulation by conventional cytotoxic drugs. Conventional antineoplastic drugs can activate anticancer immune responses through different mechanisms: (i) the inhibition of tumor-induced-suppressive mechanisms, (ii) the direct stimulation of T and B cell responses, (iii) the enhancement of tumor immunovisibility by cytotoxic cell subsets or phagocytes. Low-dose CTX and gemcitabine deplete regulatory T-cells or myeloid suppressor cells and facilitate tumor attack by effectors. Paclitaxel, cisplatin and doxorubicin induce the upregulation of mannose-6-phosphate receptors on the surface of tumor cells, rendering them permeable to granzyme B. Paclitaxel induces proinflammatory cytokines' secretion from macrophages, leading to DC, NK and T-cell activation. Anthracyclines, oxaliplatin and CTX promote tumor expression of ecto-CRT, and release of HMGB1 and ATP by dying tumor cells, thus stimulating antigen phagocytosis and cross-presentation by DC

Figure 2

Induction of immunogenic tumor cell death and stimulation of DC cross-presentation by CTX in vitro and in vivo. (a) Ecto-CRT exposure at 4 h and extracellular HMGB1 release (48 h) in tumor cells following UV irradiation or treatment with the CTX-analog Mafosfamide (MAFO). (b) In vitro uptake of CFSE-labeled OVA-expressing EG7 tumor cells, killed by UV irradiation or MAFO treatment, by splenic CD8α+DC. (c) Stimulation of OT-I CD8 T-cell cross-priming by CD8α+DC that had captured MAFO-killed EG7 tumor cells. Proliferative response (left) and IFN-γ ELISPOT assay (right) are shown. (d) Induction of tumor apoptosis in EG7 tumor-bearing mice 2 days after a single injection of CTX (100 mg/kg), as detected by FLIVO staining in the tumor tissue. (e) In situ cross-presentation of tumor-associated antigen by tumor-infiltrating DC in mice bearing EG7 tumors following CTX injection (7 days). Co-expression of CD11c and OVA-derived peptide SIINFEKL bound to MHC class I (MHC-I-OVAp) in EG7 tumor tissue sections were detected by confocal laser-scanning microscopy. Modified from Schiavoni et al