Journal Article

Checkpoint blockade-induced CD8+ T cell differentiation in head and neck cancer responders

Egloff, Ann Marie, Gu, Shengqing, Zolkind, Paul, Lederer, James A, Zhou, Liye, Guo, Fei, Liu, X Shirley, Riley, Rachel, Zhang, Zhe, Zhang, Yi, Griffith, Obi, Zhang, Fan, Haddad, Robert, Schoenfeld, Jonathan D, Ma, Xiaojing, Manguso, Robert T, Campbell, Katie M, Uppaluri, Ravindra, Keegan, Joshua, Fu, Jingxin, Du, Peter, Nakahori, Yasutaka, Zeng, Zexian, Wang, Xiaoqing

2022

Overview

BackgroundImmune checkpoint blockade (ICB) response in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) is limited to 15%–20% of patients and underpinnings of resistance remain undefined.MethodsStarting with an anti-PD1 sensitive murine HNSCC cell line, we generated an isogenic anti-PD1 resistant model. Mass cytometry was used to delineate tumor microenvironments of both sensitive parental murine oral carcinoma (MOC1) and resistant MOC1esc1 tumors. To examine heterogeneity and clonal dynamics of tumor infiltrating lymphocytes (TILs), we applied paired single-cell RNA and TCR sequencing in three HNSCC models.ResultsAnti-PD1 resistant MOC1esc1 line displayed a conserved cell intrinsic immune evasion signature. Immunoprofiling showed distinct baseline tumor microenvironments of MOC1 and MOC1esc1, as well as the remodeling of immune compartments on ICB in MOC1esc1 tumors. Single cell sequencing analysis identified several CD8 +TIL subsets including Tcf7 +Pd1− (naïve/memory-like), Tcf7 +Pd1+ (progenitor), and Tcf7-Pd1+ (differentiated effector). Mapping TCR shared fractions identified that successful anti-PD1 or anti-CTLA4 therapy-induced higher post-treatment T cell lineage transitions.ConclusionsThese data highlight critical aspects of CD8 +TIL heterogeneity and differentiation and suggest facilitation of CD8 +TIL differentiation as a strategy to improve HNSCC ICB response.

• Publisher: BMJ Publishing Group Ltd,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Animals / Antibodies / Antigens / Cancer / CD8-Positive T-Lymphocytes - metabolism / Cell Differentiation / Clinical/Translational Cancer Immunotherapy / Experiments / Female / Genomes / Genomics / Head & neck cancer / head and neck neoplasms / Head and Neck Neoplasms - drug therapy / Humans / Immune Checkpoint Inhibitors - pharmacology / Immune Checkpoint Inhibitors - therapeutic use / Immunotherapy / Lymphocytes / Male / Mice / Quality control / Software / Squamous cell carcinoma / T cell receptors / Tumor Microenvironment / tumor-infiltrating / Tumors / Variance analysis