CD161 Characterizes an Inflamed Subset of Cytotoxic T Lymphocytes Associated with Prolonged Survival in Human Papillomavirus–Driven Oropharyngeal Cancer

Abstract

Human papillomavirus (HPV)-driven oropharyngeal carcinoma (OPSCC) is distinct from tobacco- or alcohol-associated OPSCC and has a unique immune landscape. Studies have supported the heterogeneity of T cells, accompanied by a broad repertoire of T-cell responses, within tumors driven by HPV infection. However, the phenotype and function of these HPV-related T cells remain unclear. Using a combination of single-cell RNA sequencing, flow cytometry, pharmacologic inhibition, and immunofluorescence staining, we explored the prognostic implication of HPV-related T cells and further validated our findings in two independent cohorts. Cytotoxic T lymphocytes (CTLs) within OPSCC displayed a spectrum of transcriptional signatures. Among which, we identified CD161 receptor, encoded by KLRB1, as a potential marker to distinguish the CTL subsets in HPV-positive OPSCC with divergent evolutionary trajectory. In-depth analysis revealed that CD161+ CTLs exhibited a more robust immune response over the CD161- counterparts and a T-cell inflamed phenotype that could be further reinvigorated by immune checkpoint blockade. Despite the high expression of exhaustion markers, reinforcement of CD161+ CTL reactivity was expected to boost immune responses, considering their functional reversibility. We further confirmed that the high level of intratumoral CD161+ CTLs associated with a favorable treatment response and prolonged overall survival. Therefore, our research not only provides an insight into the immune landscape of HPV-driven OPSCC, but also sheds light on a special subset of CTLs with prognostic and therapeutic significance.

Poor clinical outcomes and immunoevasive contexture in CD161+CD8+T cells barren human pancreatic cancer

“…[33][34][35] In our study, CD161 + CD8 + T cells exhibited elevated expression of exhaustion markers while maintaining cytotoxic cytokine expression, consistent with the findings in HPV-positive OPSCC. 13 These results imply that despite exhibiting immune checkpoint features, CD161 + CD8 + T cells in PDAC may not be functionally exhausted. Furthermore, these cells appear to exhibit a responsive phenotype in PDAC, clarifying their role in predicting a favorable prognosis and highlighting their potential as targets for immunotherapeutic strategies.…”

“…Nevertheless, the prognostic implications of CD161 + CD8 + T cells have shown variability across different cancer types. [13][14][15][16] In early-stage liver cancer, their presence correlates with increased secondary recurrence rates and a poorer prognosis. 15 Whereas in human papillomavirus (HPV)-related oropharyngeal cancer, they are indicative of more favorable outcomes and a more robust immune response.…”

“…However, these findings have been subject to considerable debate. [13][14][15][16] These collective observations suggest that although CD161 + CD8 + T cells hold promise as prognostic markers, their functional and molecular characteristics require further elucidation. This warrants more comprehensive investigations to understand their role within the immune microenvironment of PDAC.…”

“… 15 Whereas in human papillomavirus (HPV)-related oropharyngeal cancer, they are indicative of more favorable outcomes and a more robust immune response. 13 Moreover, single-cell RNA (scRNA) sequencing studies across multiple tumors revealed a complex picture, with CD161 + CD8 + T cells playing a significant role in chemotherapeutic resistance, recurrence, and immune evasion. However, these findings have been subject to considerable debate.…”

Evolution of resistance to KRASG12Cinhibitor in a non-small cell lung cancer responder

“…These findings provide compelling evidence of active engagement of immune effectors in the antitumour response, potentially offering novel biomarkers for monitoring treatment efficacy in real time. Tumour-infiltrating CD8 + CD161 hi T cells are found in various tumour microenvironments, and their increase correlates with better prognosis 26,27 . CD161 is recognized as a coinhibitory receptor on natural killer (NK) cells; however, its role in T cells remains less defined 26,28 .…”