Dissecting the Stromal Signaling and Regulation of Myeloid Cells and Memory Effector T Cells in Pancreatic Cancer

Abstract

Purpose: Myeloid cells are a prominent immunosuppressive component within the stroma of pancreatic ductal adenocarcinoma (PDAC). Previously, targeting myeloid cells has had limited success. Here, we sought to target the myeloid cells through modifying a specific stromal component. Experimental Design: A murine model of metastatic PDAC treated with an irradiated whole-cell PDAC vaccine and PDAC specimens from patients treated with the same type of vaccine were used to assess the immune-modulating effect of stromal hyaluronan (HA) degradation by PEGPH20. Results: Targeting stroma by degrading HA with PEGPH20 in combination with vaccine decreases CXCL12/CXCR4/ CCR7 immunosuppressive signaling axis expression in cancer-associated fibroblasts, myeloid, and CD8 þ T cells, respectively. This corresponds with increased CCR7 À effector memory T-cell infiltration, an increase in tumor-specific IFNg, and improved survival. In the stroma of human PDACs treated with the same vaccine, decreased stromal CXCR4 expression significantly correlated with decreased HA and increased cytotoxic activities, suggesting CXCR4 is an important therapeutic target. Conclusions: This study represents the first to dissect signaling cascades following PDAC stroma remodeling via HA depletion, suggesting this not only overcomes a physical barrier for immune cell trafficking, but alters myeloid function leading to downstream selective increases in effector memory T-cell infiltration and antitumor activity.

Strategies in Developing Immunotherapy for Pancreatic Cancer: Recognizing and Correcting Multiple Immune “Defects” in the Tumor Microenvironment

“…Alternatively, T cell activation agents would be needed to proactively expand antitumor effector T cells. Agents that target the stroma components not only can remove the barrier to T cell infiltration, but may also reverse the immunosuppressive functions of the stroma [52]. A stroma targeting agent may be an indispensable component of an expander treatment for tumors with dense stroma.…”

Pancreatic Cancer Associated Fibroblasts (CAF): Under-Explored Target for Pancreatic Cancer Treatment

“…Targeting stroma in a murine model of metastatic pancreatic cancer using the immune modulating effect of hyaluronan degradation by PEGPH20 significantly decreased the immunosuppressive effect of CXCL12/CXCR4/CCR7 signaling axis in CAFs, myeloid, and CD8+ T cells. This also resulted in increased CCR7(-) effector memory T cell infiltration, increased interferon-gamma secretion, and increased numbers of CD8+ T cells and most importantly improved survival in an animal model of metastatic pancreatic cancer [105]. Stromal modulation has also shown promising results in the enhancement of immune checkpoint blockade treatment for pancreatic cancer.…”

CAR-T Cells Hit the Tumor Microenvironment: Strategies to Overcome Tumor Escape

“…While the role of ECM in resistance to adoptive T cell transfer therapies remains underexplored, some studies demonstrate that peritumoral ECM collagen fibers limit T cell access to tumors, and indeed, tumors with high-collagen density present lower levels of infiltrating T cells (142,143). Here, the use of the matrixdegrading agents that facilitate T cell infiltration of tumors provides a rationale for matrix degradation as a means to improve efficacy of CAR-T cell therapy (140)(141)(142). In this regard, CAR-T cells engineered to express heparanase (HPSE), which degrades heparan sulfate proteoglycans, better infiltrated tumors and had increased antitumor activity in mouse models (23).…”