Tumor microenvironment modulation enhances immunologic benefit of chemoradiotherapy

J Immunother Cancer. 2019 Jan 15;7(1):10. doi: 10.1186/s40425-018-0485-9.

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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Line, Tumor
  • Chemoradiotherapy*
  • Cyclophosphamide / therapeutic use*
  • Head and Neck Neoplasms / immunology
  • Head and Neck Neoplasms / therapy*
  • Humans
  • Immunomodulation*
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lysine / analogs & derivatives*
  • Lysine / therapeutic use
  • Male
  • Mice, Inbred C57BL
  • Neoplasms / therapy*
  • Papillomavirus Infections / complications
  • Squamous Cell Carcinoma of Head and Neck / immunology
  • Squamous Cell Carcinoma of Head and Neck / therapy*
  • Tumor Microenvironment / immunology*

Substances

  • Antineoplastic Agents
  • N(6)-(1-iminoethyl)lysine
  • Cyclophosphamide
  • Lysine