Trial watch: chemotherapy-induced immunogenic cell death in oncology

Abstract

Immunogenic cell death (ICD) refers to an immunologically distinct process of regulated cell death that activates, rather than suppresses, innate and adaptive immune responses. Such responses culminate into T cell-driven immunity against antigens derived from dying cancer cells. The potency of ICD is dependent on the immunogenicity of dying cells as defined by the antigenicity of these cells and their ability to expose immunostimulatory molecules like damage-associated molecular patterns (DAMPs) and cytokines like type I interferons (IFNs). Moreover, it is crucial that the host’s immune system can adequately detect the antigenicity and adjuvanticity of these dying cells. Over the years, several well-known chemotherapies have been validated as potent ICD inducers, including (but not limited to) anthracyclines, paclitaxels, and oxaliplatin. Such ICD-inducing chemotherapeutic drugs can serve as important combinatorial partners for anti-cancer immunotherapies against highly immuno-resistant tumors. In this Trial Watch, we describe current trends in the preclinical and clinical integration of ICD-inducing chemotherapy in the existing immuno-oncological paradigms.

Decreased Lung Metastasis in Triple Negative Breast Cancer Following Locally Delivered Supratherapeutic Paclitaxel-Loaded Polyglycerol Carbonate Nanoparticle Therapy

“…Specifically, chemotherapies are reliant on their ability to induce immunogenic cell death, which relies on damage-associated molecular patterns (DAMPs) from dying cells. Work done by Lau et al and Sprooten et al demonstrate that paclitaxel’s efficacy is linked to DAMPs, and this pathway will be evaluated in future studies after PGC–PTX + PTX treatment. This knowledge will be leveraged to supplement the antitumor efficacy of paclitaxel to inform the development of an effective treatment that targets both primary tumors and distant metastases, while limiting off-target toxicities.…”

Immunosurveillance in clinical cancer management

“…Treatment modalities other than immunotherapy can be advantageously combined with ICIs if they have a positive effect on immunosurveillance, as abundantly documented for ICD-inducing chemotherapy. 166 Similarly, at least some targeted anticancer agents as well as focal RT and locally delivered oncolytic therapies may also constitute promising combinatorial partners for ICIs, at least when used so to minimize local and systemic immunosuppression. 86,167 We thank Laurence Zitvogel for critical reading.…”

Ferroptosis and HMGB2 induced calreticulin translocation required for immunogenic cell death are controlled by the nuclear exporter XPO1

“…Inhibition of nuclear export of HMGB1 and HMGB2 reverses oxaliplatin induced translocation of calreticulin (CRT) from the cytosol to the plasma membrane The ability to inhibit HMGB1 and HMGB2 secretion from the nucleus into the cytosol made it possible to examine the consequences of this inhibition on the translocation of CRT from the endoplasmic reticulum to the plasma membrane, a process that is critical for initiating of ICD 2,26,27 . Incubation of A549 NSCLC cells with oxaliplatin alone caused a signi cant reduction of cytosolic CRT to 42.5 ± 9.7% (n = 3) of the PBS controls (p = 0.001; Fig.…”