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.

Thermoneutrality, Mice, and Cancer: A Heated Opinion

“…Overall, our data reveal that the elevated NE caused by chronic stress at ST is sufficient to bias the outcomes of experimental therapeutics testing. Because it is becoming clear that the long-term overall efficacy of chemotherapy [54][55][56], radiation [57], and photodynamic therapy [58] involves the generation of an antitumor immune response, investigators should be aware that, under standard conditions, these responses could be very different at ST and TT.Cancer, Inflammation, and Metabolic Disorders: Are Mouse Models Too Cold?In addition to antitumor immunity, cancer research has also pointed to a major role for dysregulated inflammation and metabolism in promoting tumor growth. Nevertheless, are these linkages being influenced by cold stress?…”

Structural Optimization of Indole Derivatives Acting at Colchicine Binding Site as Potential Anticancer Agents

“…2 Using potent cytotoxic drugs that inhibit microtubules has been useful in inducing cancer cells to undergo apoptosis through various mechanisms. 3 Most of the small molecule antitubulin agents bind to one of the three best characterized binding sites on α,β-tubulin subunits. For example, the taxane, vinca alkaloids, and colchicine binding sites bind to paclitaxel, vinblastine, or colchicine, respectively.…”

Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy

“…1,3,4 Importantly, some -but not all -cell death inducers are capable of eliciting ICD, 35 and this property cannot be anticipated by structural or functional considerations. 3,[36][37][38] Indeed, while cisplatin and oxaliplatin both exert cytostatic/cytotoxic effects as they induce inter-and intra-strand DNA adducts, [39][40][41][42] only the latter triggers bona fide ICD as it provokes a pre-mortem ER stress response. 43,44 Thus, although assays for the detection of surrogate ICD markers are available, 45 the gold standard approach for determining whether a cytotoxic intervention provokes bona fide ICD still relies on vaccination experiments involving murine cancer cells and syngeneic, immunocompetent mice.…”