Abstract 1520: A novel cluster of cytolytic alpha/beta TCR+CD4−CD8−T cells originating from CD8+T cells with potent innate-like T cell killing ability: implicating adoptive T cell transfer therapy for hepatocellular carcinoma

Abstract

Abstract Tumor immunotherapies represent promising strategies for treating various cancers, including hepatocellular carcinoma. In this context, immune cells, including the adoptive T cell transfer treatment, become the focus of interests. Notably, alpha/beta TCR+CD4−CD8−T (DNT) cells is a subgroup of T cells that is ignored for a long time but was re-focused recently. These DNT cells are a group of cells with opposite functions in different condition, including pro-inflammatory or suppressive functions and possibly originated from over-stimulation of peripheral CD4+T cells/CD8+T cells or a special group of T cells formed in thymus. In our research results, we have found these DNT cells increased in murine hepatoma model, especially in the tumor microenvironment. In addition, these DNT cells from tumor microenvironment of murine hepatoma possessed potent tumor-killing ability. Furthermore, we analyzed the transcriptome profile of T cells in tumor microenvironment by single cell RNAseq approach (CITE-seq). We found DNT cells could be categorized into two main clusters, one is cytolytic DNT cells, resemble the potent CD8+T cells, and another is the CD4+T cell-like DNT cells. These cytolytic DNT cells are not exhausted but with high expression of cytolytic molecule and low hypoxia-inducible factor-1alpha (HIF-1a) expression. By trajectory analysis, cytolytic DNT cells come from the conventional CD8+T cells but following a unique developmental pathway that is different from the exhausted CD8+T cells. Interesting, these cytolytic DNT cells also expressed high level of Fcer1g molecule, a marker of innate CD8+T cells. In addition, these DNT cells could be generated and expanded in-vitro by IL-15 without TCR activation. In conclusion, we identified a cluster of cytolytic DNT cells, originated from CD8+T cells, exhibits innate T cells behavior and potent killing ability. In addition, these cytolytic DNT cells could be generated and expanded in-vitro for the adoptive T cell transfer treatment of hepatoma. Citation Format: Cheng-Heng Wu, Te-Wei Tseng, Chen-Yang Huang, Ping-Hsun Ou, Yi-Chen Lin, Pin-Jung Chen, Po-Ting Lin, Chan-Keng Yang, Wei Teng, Tsung-Han Wu, Yung-Chang Lin, Chun-Yen Lin. A novel cluster of cytolytic alpha/beta TCR+CD4−CD8−T cells originating from CD8+T cells with potent innate-like T cell killing ability: implicating adoptive T cell transfer therapy for hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1520.