Tumor microenvironment modulation enhances immunologic benefit of chemoradiotherapy.

Academic Article

Abstract

  • BACKGROUND: Chemoradiotherapy (CRT) remains one of the most common cancer treatment modalities, and recent data suggest that CRT is maximally effective when there is generation of an anti-tumoral immune response. However, CRT has also been shown to promote immunosuppressive mechanisms which must be blocked or reversed to maximize its immune stimulating effects. METHODS: Therefore, using a preclinical model of human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC), we developed a clinically relevant therapy combining CRT and two existing immunomodulatory drugs: cyclophosphamide (CTX) and the small molecule inducible nitric oxide synthase (iNOS) inhibitor L-n6-(1-iminoethyl)-lysine (L-NIL). In this model, we treated the syngeneic HPV-HNSCC mEER tumor-bearing mice with fractionated (10 fractions of 3 Gy) tumor-directed radiation and weekly cisplatin administration. We compared the immune responses induced by CRT and those induced by combinatory treatment (CRT + CTX/L-NIL) with flow cytometry, quantitative multiplex immunofluorescence and by profiling immune-related gene expression changes. RESULTS: We show that combination treatment favorably remodels the tumor myeloid immune microenvironment including an increase in anti-tumor immune cell types (inflammatory monocytes and M1-like macrophages) and a decrease in immunosuppressive granulocytic myeloid-derived suppressor cells (MDSCs). Intratumoral T cell infiltration and tumor antigen specificity of T cells were also improved, including a 31.8-fold increase in the CD8+ T cell/ regulatory T cell ratio and a significant increase in tumor antigen-specific CD8+ T cells compared to CRT alone. CTX/LNIL immunomodulation was also shown to significantly improve CRT efficacy, leading to rejection of 21% established tumors in a CD8-dependent manner. CONCLUSIONS: Overall, these data show that modulation of the tumor immune microenvironment with CTX/L-NIL enhances susceptibility of treatment-refractory tumors to CRT. The combination of tumor immune microenvironment modulation with CRT constitutes a translationally relevant approach to enhance CRT efficacy through enhanced immune activation.

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    Keywords

  • Chemoradiotherapy, Cyclophosphamide, Head and neck cancer, Head and neck squamous cell carcinoma, Human papillomavirus (HPV), Immunotherapy, Inducible nitric oxide synthase (iNOS), L-n6-(1-iminoethyl)-lysine (L-NIL), Radiotherapy, Tumor microenvironment, Animals, Antineoplastic Agents, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Chemoradiotherapy, Cyclophosphamide, Head and Neck Neoplasms, Humans, Immunomodulation, Lymphocytes, Tumor-Infiltrating, Lysine, Male, Mice, Inbred C57BL, Neoplasms, Papillomavirus Infections, Squamous Cell Carcinoma of Head and Neck, Tumor Microenvironment

    • Digital Object Identifier (doi)

    Pubmed Id

  • 28642549

    • Author List

  • Hanoteau A; Newton JM; Krupar R; Huang C; Liu H-C; Gaspero A; Gartrell RD; Saenger YM; Hart TD; Santegoets SJ

    • Start Page

  • 10

    • Volume

  • 7

    • Issue

  • 1