TY - JOUR T1 - Tumor microenvironment modulation enhances immunologic benefit of chemoradiotherapy JF - Journal for ImmunoTherapy of Cancer JO - J Immunother Cancer DO - 10.1186/s40425-018-0485-9 VL - 7 IS - 1 SP - 10 AU - Aurelie Hanoteau AU - Jared M. Newton AU - Rosemarie Krupar AU - Chen Huang AU - Hsuan-Chen Liu AU - Angelina Gaspero AU - Robyn D. Gartrell AU - Yvonne M. Saenger AU - Thomas D. Hart AU - Saskia J. Santegoets AU - Damya Laoui AU - Chad Spanos AU - Falguni Parikh AU - Padmini Jayaraman AU - Bing Zhang AU - Sjoerd H. Van der Burg AU - Jo A. Van Ginderachter AU - Cornelis J. M. Melief AU - Andrew G. Sikora Y1 - 2019/12/01 UR - http://jitc.bmj.com/content/7/1/10.abstract N2 - 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.Abbreviations:CRTChemoradiotherapyCTXCyclophosphamideDCDendritic cellKLRG1Killer cell lectin-like receptorHNSCCHead and neck squamous cell carcinomaHPVHuman papillomavirusICDImmunogenic cell deathIDOIndoleamine 2,3- dioxygenaseILInterleukinsiNOSInducible nitric oxide synthaseIR-Immune response negativeIR+Immune response positiveL-NILL-n6-(1-iminoethyl)-lysineMDSCMyeloid-derived suppressor cellMHCMajor histocompatibility complexOPSCCOropharyngeal squamous cell carcinomaPCAPrincipal component analysiss.c.SubcutaneouslyTGF-βTransforming growth factor betaTLRToll-like receptorTregRegulatory T celltSNEt Stochastic neighborhood embedding ER -