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

Author:

Wei Ye123ORCID,Xu Tingting1ORCID,Li Chong2ORCID,Zhou Xin1ORCID,Qian Wei1ORCID,Shen Chunying1ORCID,Wang Qifeng4ORCID,Xing Xing1ORCID,Ou Xiaomin1ORCID,He Xiayun1ORCID,Yin Hongmei1ORCID,Hu Chaosu1ORCID,Wang Yu5ORCID,Ji Qinghai5ORCID,Su Fengtao2ORCID,Lu Xueguan1ORCID

Affiliation:

1. 1Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College of Fudan University, Shanghai, China.

2. 2Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai Medical College of Fudan University, Shanghai, China.

3. 3Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

4. 4Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai Medical College of Fudan University, Shanghai, China.

5. 5Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College of Fudan University, Shanghai, China.

Abstract

AbstractHuman 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 (CTL) 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 a 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.

Funder

National Natural Science Foundation of China

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Immunology

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