Abstract 5083: Investigating the development and therapeutic potential of intra-tumoral CXCR6+ effector/effector memory T cells (TEFF/EM) in triple-negative breast cancer

Abstract

Abstract Triple-negative breast cancer (TNBC) is an aggressive subtype that makes up 10-20% of all breast cancer cases. Because of the higher risk of metastasis and recurrence post-treatment, there is a need to develop novel therapeutics to address these challenges. In previously published work, we demonstrated that CXCL16 traps CXCR6+PD-1+ effector/effector memory (TEFF/EM) within the primary tumor and that these T cells have anti-metastatic function that can be harnessed when released into peripheral sites with intra-tumoral administration of anti-CXCL16 prior to surgical resection. However, whether CXCL16 blockade can be used in combination with conventional checkpoint targets and the developmental route of this CXCR6+ TEFF/EM is not known. To develop a novel neoadjuvant therapy, we use the spontaneously metastasizing murine TNBC model, 4T1. Here, we report that anti-4-1BB, and not anti-PD-1, when used in combination with blockade of CXCL16 can prolong survival post-surgical resection. Using anti-4-1BB in combination with CRISPR-generated Cxcl16-KO 4T1 model, we show that both deficiency of CXCL16 within the tumor microenvironment (TME) and anti-4-1BB contribute synergistically to survival advantage. To study the development of this population of T cells, we use the Py8119 murine TNBC model. We definitively show that CXCR6+PD-1+ TEFF/EM is uniquely generated within the primary tumor. Co-expression of CXCR6 and PD-1 indicates that T cell receptor (TCR) signaling is a potential regulator of the development of this TEFF/EM sub-population. Analyses of our previously published scRNA-seq dataset reveals Lat2 to be the top gene involved in TCR signaling. Tumors growing on Lat2-KO animals show a significant increase in tumor size accompanied by significant reduction of CD44high/mid CXCR6+PD-1+ TEFF/EM. However, competitive transfer of naïve WT and Lat2-KO T cells into Tcra-KO recipients led to comparable levels of CXCR6+ TEFF/EM. Surprisingly, transferred Lat2-KO T cells failed to engraft within the primary tumor relative to WT T cells. Future work will address if this engraftment defect is due to expansion/survival defects. Therefore, regulation of TCR signaling within the TME via LAT2 potentially represents a mechanism in which primary tumors trap T cells, promoting their exhaustion. Importantly, this can be harnessed through combinatorial activation and blockade of 4-1BB and CXCL16 respectively. Citation Format: Bryan Jian Wei Lim, Xiao-Fan Wang, Qi-Jing Li. Investigating the development and therapeutic potential of intra-tumoral CXCR6+ effector/effector memory T cells (TEFF/EM) in triple-negative breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5083.