So-Jin Park1, Wenda Ye2, Roy Xiao2, Christopher Silvin3, Michelle Padget4, James W Hodge4, Carter Van Waes3, Nicole C Schmitt5. 1. Integrative Therapeutics Program, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, United States. 2. Integrative Therapeutics Program, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, United States; Tumor Biology Section, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, United States; Medical Research Scholars Program, National Institutes of Health, Bethesda, MD, United States; Cleveland Clinic Lerner College of Medicine, Cleveland, OH, United States. 3. Tumor Biology Section, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, United States. 4. Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States. 5. Integrative Therapeutics Program, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, United States; Department of Otolaryngology - Head and Neck Surgery, Johns Hopkins University, Baltimore, MD, United States. Electronic address: nicole.schmitt@nih.gov.
Abstract
OBJECTIVES: Prior studies suggest that oxaliplatin is unique among platinum chemotherapy drugs in its ability to enhance anti-tumor immunity, but the immune mechanisms of different platinum chemotherapy drugs have not been previously compared in preclinical models of head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Human HNSCC cell lines were treated with cisplatin or oxaliplatin, then assessed for markers associated with immunogenic cell death (ICD) and antigen processing. A syngeneic mouse model of oral cancer was then used to compare the effects of cisplatin vs. oxaliplatin, alone or in combination with anti-PD-1 immunotherapy, on tumor growth and survival. A subset of spleens and tumors were analyzed for ICD markers and immune cell infiltrates by flow cytometry. RESULTS: Cisplatin and oxaliplatin both increased cell surface levels of calreticulin, HSP70, MHC class I and PD-L1 in multiple cell lines. Inoculation of immunocompetent mice with cells killed in vitro by either drug resulted in failure of subsequently-injected live tumor cells to establish and grow in a small proportion of animals. Systemic cisplatin and oxaliplatin induced similar tumor growth delay when combined with anti-PD-1 therapy. CONCLUSIONS: Treatment of HNSCC cells with platinum chemotherapy appears to induce some features of anti-tumor immunity, which may be enhanced by anti-PD-1 therapy. Cisplatin, the standard drug for HNSCC, appears to affect anti-tumor immunity in a similar fashion to oxaliplatin in these preclinical models.
OBJECTIVES: Prior studies suggest that oxaliplatin is unique among platinum chemotherapy drugs in its ability to enhance anti-tumor immunity, but the immune mechanisms of different platinum chemotherapy drugs have not been previously compared in preclinical models of head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS:HumanHNSCC cell lines were treated with cisplatin or oxaliplatin, then assessed for markers associated with immunogenic cell death (ICD) and antigen processing. A syngeneic mouse model of oral cancer was then used to compare the effects of cisplatin vs. oxaliplatin, alone or in combination with anti-PD-1 immunotherapy, on tumor growth and survival. A subset of spleens and tumors were analyzed for ICD markers and immune cell infiltrates by flow cytometry. RESULTS:Cisplatin and oxaliplatin both increased cell surface levels of calreticulin, HSP70, MHC class I and PD-L1 in multiple cell lines. Inoculation of immunocompetent mice with cells killed in vitro by either drug resulted in failure of subsequently-injected live tumor cells to establish and grow in a small proportion of animals. Systemic cisplatin and oxaliplatin induced similar tumor growth delay when combined with anti-PD-1 therapy. CONCLUSIONS: Treatment of HNSCC cells with platinum chemotherapy appears to induce some features of anti-tumor immunity, which may be enhanced by anti-PD-1 therapy. Cisplatin, the standard drug for HNSCC, appears to affect anti-tumor immunity in a similar fashion to oxaliplatin in these preclinical models.
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