Tumor microenvironment modulation enhances immunologic benefit of chemoradiotherapy

Hanoteau, Aurelie; Newton, Jared M.; Krupar, Rosemarie; Huang, Chen; Liu, Hsuan-Chen; Gaspero, Angelina; Gartrell, Robyn D.; Saenger, Yvonne M.; Hart, Thomas D.; Santegoets, Saskia J.; Laoui, Damya; Spanos, Chad; Parikh, Falguni; Jayaraman, Padmini; Zhang, Bing; Van der Burg, Sjoerd H.; Van Ginderachter, Jo A.; Melief, Cornelis J. M.; Sikora, Andrew G.

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.

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.

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.

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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Also Published In

Journal for ImmunoTherapy of Cancer

More About This Work

Academic Units
Published Here
April 3, 2019


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)