Abstract 769: CD161 identifies head and neck cancer patients with remarkable outcomes (2021)

Abstract CD161 (KLRB1) is broadly expressed in natural killer (NK) cell and T cell lines. It is well-recognized to inhibit NK cell functions, while its emerging role in T cell regulation has only been reported in stomach cancer. The biological and translational impact of CD161 in head and neck squamous cell carcinoma (HNSCC) is underexplored. Here, we first show that intratumoral CD161 expression level alone in HNSCC patient tumors predict &amp;gt;2 times longer survival than those with CD161 underexpression (67.81 vs 32.62 months; P=0.0003, median cut-off). The prognosticity of CD161 could also be identified in HPV(+) (Undefined vs 57.42 months; P=0.009, median cutoff) and HPV(-) (64.78 vs 32.36 months; P=0.025, median cutoff) HNSCC patients. Similar findings are observed in 6 other cancers (breast, liver, cervical, lung and adrenocortical cancers) by COX-regression (HR&amp;lt;1 and CoxP &amp;lt; 0.05). Strikingly, in both HPV(+) and HPV(-)HNSCC, CD161's positive prognostic power is comparable to that of multigene estimation of CD8+T cell abundancies by CIBERSORT-ABS (https://cibersort.stanford.edu/), and superior than that of intratumoral levels of LLT1 (ligand of CD161), and T-cell-associated markers CD8A, CD69, CD103 (T cell, Dendritic cell marker) at median cutoffs. Subsequent tumor-infiltrating lymphocyte (TIL) analyses (by CIBERSORT-ABS) show that CD161-high patients have significantly higher B cell naïve, B cell memory, B cell plasma, activated NK cell, CD8+ T cell, and follicular helper T cell than CD161-low patients in HNSCC and HPV-stratified HNSCC. This is strongly supported by transcriptome findings on CD161's distinct T cell-B cell activation signatures with elevated VCAM1, GPR18 and PTPRC. Furthermore, we determined in HPV(-)HNSCC, 12 gene mutations (CYLD, CCDC172, SAMD7, CDKL1, WDR47, MFSD9, PWWP2B, UXT, GP6, FAM9A, ARSE, UGCG) are associated with elevated CD161, while in HPV(+)HNSCC, 9 gene mutations (COL6A2, ZHX, SCN3A, GNA15, CDH3, SAMD7, MTUS1, FANCI, ARSE) are linked to elevated CD161. Our data first identified CD161 as a single prognostic biomarker gene with potential clinical utility, discovering its strong ties to high CD8+T cell, B cell and activated NK cell in HNSCC. This study was funded by the Lee Hysan Foundation Research Grant and Endowment Fund Research Grant Schemes 2018-2019 (CA11281) and 2019-2020 (CA11286), United College, the Chinese University of Hong Kong, Hong Kong SAR, China. V.W.Y.L. also receives fundings from General Research Fund, Research Grant Council, Hong Kong Government, Hong Kong SAR (#17121616, #14168517), Research Impact Fund (#R4015-19F, R4017-18), Health and Medical Research Fund (HMRF#15160691), University-Industry Collaboration Programme (UIM/329; Innovation and Technology Fund), and the Hong Kong Cancer Fund, Hong Kong SAR. Y.L. received funding supports (Postdoctoral Hub PH-ITF Ref.: PiH/052/18 of UIM/329) from the Innovation and Technology Fund, Hong Kong government. Citation Format: Yuchen Liu, Vivian Wai Yan Lui. CD161 identifies head and neck cancer patients with remarkable outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 769.