期刊
JOURNAL FOR IMMUNOTHERAPY OF CANCER
卷 7, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s40425-018-0485-9
关键词
Immunotherapy; Tumor microenvironment; Inducible nitric oxide synthase (iNOS); Cyclophosphamide; L-n6-(1-iminoethyl)-lysine (L-NIL); Chemoradiotherapy; Radiotherapy; Head and neck squamous cell carcinoma; Head and neck cancer; Human papillomavirus (HPV)
资金
- National Institute of General Medical Sciences T32 predoctoral training grant of the National Institutes of Health [T32GM088129]
- National Institute of Dental & Craniofacial Research F31 NRSA training grant of the National Institutes of Health [F31DE026682]
- Dutch Cancer Society [2014-6696]
- Swim Across America
- German Cancer Aid
- Cancer Prevention and Research Institutes of Texas [CPRIT RR160027]
- McNair Medical Institute at The Robert and Janice McNair Foundation
- Kom op tegen Kanker (Stand Up against Cancer)
- FWO (Science Foundation Flanders)
- Foundation against Cancer
- Caroline Weiss Law Endowment for Academic Excellence
- Owens Foundation
- Cancer Research Institute
- National Institutes of Health [NCI/NIDCR 1U01DE028233-01]
BackgroundChemoradiotherapy (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.MethodsTherefore, 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 3Gy) 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.ResultsWe 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.ConclusionsOverall, 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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