Cisplatin Alters Antitumor Immunity and Synergizes with PD-1/PD-L1 Inhibition in Head and Neck Squamous Cell Carcinoma

Abstract

Head and neck squamous cell carcinoma (HNSCC) has been treated for decades with cisplatin chemotherapy, and anti–PD-1 immunotherapy has recently been approved for the treatment of this disease. However, preclinical studies of how antitumor immunity in HNSCC is affected by cisplatin alone or in combination with immunotherapies are lacking. Here, we show that sublethal doses of cisplatin may enhance antigen presentation and T-cell killing in vitro, though cisplatin also upregulates tumor cell expression of PD-L1 and may impair T-cell function at higher doses. In a syngeneic mouse model of HNSCC, concurrent use of cisplatin and anti–PD-L1/PD-1 delayed tumor growth and enhanced survival without significantly reducing the number or function of tumor-infiltrating immune cells or increasing cisplatin-induced toxicities. These results suggest that moderate doses of cisplatin may enhance antitumor immunity by mechanisms other than direct tumor cell killing, which may be further enhanced by anti–PD-L1/PD-1 therapy.

Sequential therapy of neoadjuvant biochemotherapy with cetuximab, paclitaxel, and cisplatin followed by cetuximab‐based concurrent bioradiotherapy in high‐risk locally advanced oral squamous cell carcinoma: Final analysis of a phase 2 clinical trial

“…In ovarian cancer, paclitaxel showed local immunosuppression in association with increased NF‐kappa B‐regulated PD‐L1 expression . Furthermore, the treatment of cell lines with cisplatin was shown to increase the expression of the protein in HNC . It is not known how cetuximab affects PD‐L1, but CTLA4‐positive regulatory T cells were reported to be enriched .…”

“…52 Furthermore, the treatment of cell lines with cisplatin was shown to increase the expression of the protein in HNC. 53 It is not known how cetuximab affects PD-L1, but CTLA4-positive regulatory T cells were reported to be enriched. 54 Although the exact immunology impact of the conventional antitumor reagents remains to be elucidated, the related dynamic PD-L1 expression is of concern because of its potential to alter the tumor features and the possibility in affecting the prognostic outcome.…”

Recent Considerations in the Application of RAPTA‐C for Cancer Treatment and Perspectives for Its Combination with Immunotherapies

“…[34] It has been already shown in vitro, as well as in in vivo models, that immunotherapeutic agents, for example, indoximod, may act synergistically in combination with cisplatin (Figure 3A). [133] In a murine mesothelioma model, monoclonal antibodies binding to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), checkpoint inhibitors, given between cycles of cisplatin blocked tumor cell repopulation and induced tumor infiltration of CD4 and CD8 T cells. [129][130][131] In vivo studies in immunocompetent mice revealed the benefit of combining clinically used chemotherapeutics and PD-1/PD-L1 inhibitors for different tumor types, for example, cisplatin for MB49 and MBT-2 bladder cancers and oxaliplatin for MC38 colon cancer.…”

“…After vaccination, IgG levels targeting VEGFR2 were significantly increased, which correlated with overall survival in HLA-matched patients. [132,133,137] Interestingly, the effect of NAMI-A on lymphocyte infiltration at primary tumor sites has been studied. [134] In comparison to platinum-based drugs, the immunomodulatory effect of several ruthenium compounds, with respect to inhibition of VEGFR signaling, has been identified in vitro, as well as in in vivo settings.…”

Neutralizing PD-L1 and PD-L2 Enhances the Efficacy of Immune Checkpoint Inhibitors in Ovarian Cancer

“…Clearly, there is a knowledge gap between our current understanding of immune regulation and how it can be manipulated to enhance the clinical efficacy of ICB therapies in ovarian cancer. An ongoing effort to enhance the response rate of ICB inhibitors is being pursued in the clinic through combining these inhibitors with cytotoxic drugs, targeted therapies and radiation treatment (10)(11)(12). However, responses to ICB in ovarian cancer are still low, even in combination with cytotoxic chemotherapy and targeted therapy (9).…”