Silencing of tumoral carbohydrate sulfotransferase 15 reactivates lymph node pancreatic cancer T cells in mice

Abstract

AbstractLimited intratumoral T‐cell infiltration in pancreatic ductal adenocarcinoma (PDAC) is an obstacle to immunotherapy, yet the efficient approach to enhance tumor‐infiltrating T cells is not fully established. Here, we show that tumor‐specific knockdown of carbohydrate sulfotransferase 15 (CHST15), a tumor stromal proteoglycan‐synthetic enzyme, suppresses tumor growth in a T‐cell‐dependent manner in a murine model of PDAC. Silencing of tumoral CHST15 unexpectedly expanded CD4+ and CD8+ T cells in tumor draining LN (TDLN), leading to accelerated accumulation of EdU+ proliferating CD4+ and CD8+ T cells and granzyme B+ CD8+ T cells in the tumor. RNA expression analysis indicated that tumoral CHST15 knockdown (KD) downregulated matrix remodeling‐related genes, while upregulated anti‐tumor T‐cell activity‐related genes in both tumor and TDLN. CHST15 KD significantly diminished intratumoral and TDLN Ly6C/G+ myeloid‐derived suppressor cells prior to TDLN T‐cell expansion, suggesting that tumoral CHST15 remotely regulated myeloid‐derived suppressor cell mediated T‐cell suppression in the TDLN. Our findings illustrate a novel immunotherapeutic potential of tumoral CHST15 blockage by reactivating T cells in immune suppressive TDLN of PDAC.