Treatment-naïve HPV+ head and neck cancers display a T-cell-inflamed phenotype distinct from their HPV- counterparts that has implications for immunotherapy

Abstract

Cancers progress when the immune system fails to identify and eliminate malignant cells. Recognition of this, combined with advances in tumor immunology, has allowed development of therapies that induce effective anti-tumor immune responses. For incompletely-understood reasons, effective responses to immunotherapy occur in some patients and not others. Head and neck squamous cell carcinomas (HNSCC) are a common cancer type that can be divided into two subsets based on human papillomavirus (HPV) status. HPV status is a strong predictor of positive clinical outcome. Expression of exogenous viral antigens by HPV+, but not HPV-, HNSCC allows direct comparison of the immune status (immune cell presence and characteristics) between these two otherwise anatomically-similar tumors. Using TCGA data, we compared the immune landscape between HPV+ and HPV- treatment-naïve HNSCC. As compared to HPV- samples, HPV+ HNSCC exhibited a strong Th1 response characterized by increased infiltration with multiple types of immune cells and expression of their effector molecules. HPV+ HNSCC also expressed higher levels of CD39 and multiple T-cell exhaustion markers including LAG3, PD1, TIGIT, and TIM3 compared to HPV- HNSCC. Importantly, patients with higher expression of these exhaustion markers–indicative of a T-cell-inflamed tumor–correlated with markedly improved survival in HPV+, but not HPV-, HNSCC. Thus, profound differences exist between the immune landscape of HPV+ and HPV- HNSCC. These results suggest that immune checkpoint inhibitor therapy is a promising treatment strategy for HPV+ HNSCC, and that expression of immune checkpoint molecules could serve as a predictive biomarker of patient outcome in HPV+ HNSCC.

Survival-Associated Metabolic Genes in Human Papillomavirus-Positive Head and Neck Cancers

“…In each case, reduced expression correlated with improved survival, suggesting that reduced tumour cell metabolism is prognostically favorable. None of these genes were associated with altered survival in HPV-HNSCC, reinforcing the concept that HPV+ and HPV-HNSCC are distinct tumour entities [7][8][9]23]. This is not unexpected, as E6 from HPV16 and HPV18 can increase the expression of mitochondrial cellular respiration genes in a head and neck cancer cell line [24], which matches our observation of increased expression of these genes in HPV+ HNSCCs when compared to HPV-HNSCCs.…”

“…HPV-positive (HPV+) HNSCCs are distinct from their HPV-negative (HPV-) counterparts from a molecular perspective, with characteristic genetic, epigenetic, and protein expression profiles [7][8][9]. In addition, patient outcomes are generally far more favorable for HPV+ than HPV-HNSCC [10].…”

Immunological Network in Head and Neck Squamous Cell Carcinoma—A Prognostic Tool Beyond HPV Status

“…In silico studies published by Chen et al (49) and Gameiro et al (37) did not reveal any statistically significant differences in the expression of mDC-related genes between HPV-positive and HPV-negative HNSCC samples (37,49). In contrast, we observed significantly higher levels of CD45+LIN-HLA-DR+CD14-CD11c+ mDCs in HPV+ oropharyngeal tumors compared to those in HPV-negative HNSCC using flow cytometry (29).…”

Prognostic significance of neutrophil‐to‐lymphocyte ratio in HPV status era for oropharyngeal cancer

“…Several studies have compared various immunological parameters between HPV-positive and HPV-negative head and neck cancers, and have commonly concluded that the former are immune "hot" tumours, with more immune infiltration and higher levels of CD8 + T-cell activation than the latter (Gameiro et al, 2018).…”