Th2 cells are associated with tumor recurrence following radiation.

Abstract Background Curative treatment of the most aggressive solid tumors utilizes radiation therapy, either as a monotherapy or combined with surgery and/or chemotherapy. Previously, we linked the expression of PD-L1 with clinical radioresistance; however, the relationship between outcome following radiation and immune function is unclear. Methods We used two well-annotated cohorts to examine clinical outcomes. The discovery cohort included 94 patients diagnosed with Head and Neck squamous cell carcinoma (HNSCC) who were treated uniformly with surgery and adjuvant radiation. The validation cohort consisted of 97 patients with similar treatment. Immune infiltrates in tumors were derived from RNAseq gene expression in tumor tissues using xCell. The association between each immune cell type and clinical outcomes was tested using Cox proportional hazards models. Immune cell types significantly associated with overall survival (OS), distant metastasis (DM), or locoregional recurrence (LRR) in the discovery cohort were examined in the independent validation cohort. Genes that carry nonsynonymous somatic mutations or have mRNA expression that is associated with the abundance of CD4 + T helper 2 (Th2) cell infiltrate in tumors were also identified in the full TCGA HNSCC cohort as well as non-overlapping cohorts from the International Cancer Genome Consortium (ICGC) and the National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium (CPTAC). Results In the discovery cohort, we identified intratumoral cell types significantly associated with OS (monocytes, CD4 + memory T cells & Th2 cells), DM (CD4 + memory T cells, sebocytes, and epithelial cells) or LRR (common lymphoid progenitor (CLP) cells, CD4 + memory T cells, Th2 cells, and immature dendritic cells (iDCs). However, only a positive association between high levels of Th2 cells and LRR was identified in the validation cohort. We also identified CREBBP/EP300 and CASP8 among the genes that carry somatic mutations significantly associated with the presence of Th2 cells. Additionally, pathway analysis of genes correlated with Th2 cells revealed potential repression of the antitumor immune response and activation of BRCA1-associated DNA damage repair in multiple cohorts. Conclusions Th2 infiltrate is enriched in HPV-negative HNSCC tumors and is associated with LRR in two independent cohorts of patients following surgery and radiation. Th2 infiltrate is associated with mutations in CASP8 and CREBBP/EP300 and pathways previously shown to impact the response to radiation. Further investigation is warranted to investigate the mechanisms underlying the role of Th2 cells in mediating radioresistance in HPV-negative HNSCC.