Platinum Derivatives Effects on Anticancer Immune Response

Abstract

Along with surgery and radiotherapy, chemotherapeutic agents belong to the therapeutic arsenal in cancer treatment. In addition to their direct cytotoxic effects, these agents also impact the host immune system, which might enhance or counteract their antitumor activity. The platinum derivative compounds family, mainly composed of carboplatin, cisplatin and oxaliplatin, belongs to the chemotherapeutical arsenal used in numerous cancer types. Here, we will focus on the effects of these molecules on antitumor immune response. These compounds can induce or not immunogenic cell death (ICD), and some strategies have been found to induce or further enhance it. They also regulate immune cells' fate. Platinum derivatives can lead to their activation. Additionally, they can also dampen immune cells by selective killing or inhibiting their activity, particularly by modulating immune checkpoints' expression.

Keywords: carboplatin; cisplatin; immune checkpoints; immunogenic cell death; oxaliplatin.

Figure 1

Immunogenic cell death (ICD) characteristics. In response to ICD inducers, cancer cells secrete ATP (which leads to dendritic cell (DC) recruitment and activation), express calreticulin (CRT) and other endoplasmic reticulum (ER) chaperone molecules at the plasma membrane, and release high-mobility group box 1 (HMGB1), leading to DC maturation and initiation of intrinsic type I interferon (IFN) response and CXC-chemokine ligand 10 (CXCL10) production promoting T-cell recruitment. Acting as DAMPs (damage-associated molecular patterns), these molecules favor phagocytosis of cellular debris by antigen-presenting cells (APCs) such as DCs. All these events will engage an adaptive immune response, implicating αβ and γδ T cells and the establishment of an immunological memory. Such a response is able to eradicate cancer cells through an IFNγ-dependent mechanism. Adapted from Galluzzi et al. [7].

Figure 2

Description of main experimental settings to detect ICD in vitro (A) and in vivo (B). A: After various chemotherapeutic treatments of cancer cells in vitro, supernatants and cancer cells were recovered. ATP, DAMPs and HMGB1 release was measured in the supernatants, by chemiluminescence assay (ATP) and by ELISA (DAMPs and HMGB1). On the cells, HMGB1 was visualized by immunofluorescence (anti-HMGB1 antibody staining with DAPI (4′,6-diamidino-2-phenylindole)), p-eiF2α (eukaryotic initiation factor 2α) by western blot (anti- p-eiF2α and anti- eiF2α antibodies), and CRT exposure by flow cytometry (anti-CRT antibody with DAPI). To obtain results illustration, CT26 murine colon cancer cells were treated or not (Co) for 30 min with 400 µM oxaliplatin in hypotonic medium (Glucose 2.5%) and left for 24 h in a new medium before experiments. B: Mice were subcutaneously (s.c.) injected with CT26 previously treated in vitro with chemotherapy. One week later, live cells were s.c. injected on the opposite flank, and tumor growth was monitored. When chemotherapy is an ICD inducer, no tumor is detected, while if it is not, a tumor will grow at the secondary site of injection. To obtain results illustration, mice were s.c. injected with 500,000 CT26 cells treated as indicated in vitro. One week later, mice were s.c. injected in the opposite flank with 500,000 live CT26 cells. Survival (n = 6 animals per group) was represented using the Kaplan–Meier method. p < 0.01, using log-rank test.

Figure 3

Oxaliplatin in hypotonic conditions treatment of peritoneal carcinomatosis vaccinates mice. Balb/c mice were intraperitoneally injected with 25,000 CT26 cells in 2 mL glucose 2.5% + 150 mg/L oxaliplatin (Hypo/ox). When animals were cured, 25,000 CT26 cells were s.c. injected, and tumor appearance was monitored. As a control, 25,000 CT26 cells were s.c. injected in Balb/c mice. Survival (n = 6 animals for Control group and n = 5 animals for Hypo/ox group) was represented using the Kaplan–Meier method. p < 0.01, using log-rank test. For more information on material and methods, see [25].