Regulatory T-cell Depletion Alters the Tumor Microenvironment and Accelerates Pancreatic Carcinogenesis

Abstract

Regulatory T cells (Treg) are abundant in human and mouse pancreatic cancer. To understand the contribution to the immunosuppressive microenvironment, we depleted Tregs in a mouse model of pancreatic cancer. Contrary to our expectations, Treg depletion failed to relieve immunosuppression and led to accelerated tumor progression. We show that Tregs are a key source of TGFβ ligands and, accordingly, their depletion reprogramed the fi broblast population, with loss of tumor-restraining, smooth muscle actin-expressing fi broblasts. Conversely, we observed an increase in chemokines Ccl3, Ccl6 , and Ccl8 leading to increased myeloid cell recruitment, restoration of immune suppression, and promotion of carcinogenesis, an effect that was inhibited by blockade of the common CCL3/6/8 receptor CCR1. Further, Treg depletion unleashed pathologic CD4 + T-cell responses. Our data point to new mechanisms regulating fi broblast differentiation in pancreatic cancer and support the notion that fi broblasts are a heterogeneous population with different and opposing functions in pancreatic carcinogenesis. SIGNIFICANCE:Here, we describe an unexpected cross-talk between Tregs and fi broblasts in pancreatic cancer. Treg depletion resulted in differentiation of infl ammatory fi broblast subsets, in turn driving infi ltration of myeloid cells through CCR1, thus uncovering a potentially new therapeutic approach to relieve immunosuppression in pancreatic cancer.

Immune Selection Pressure Contributes to Pancreatic Cancer Immune Evasion

“…CCL9 induction by cancer cells has been shown to be associated with the recruitment of CCR1-expressing immunosuppressive myeloid cells, and that targeting CCL9/CCR1 interaction limited tumor growth in mice. However, the phenotype of these CCR1-expressing myeloid cell populations varies among cancer models (10)(11)(12)(13)(14). Together, our findings suggest that immune selection pressure, potentially through myeloid mimicry, was associated with the infiltration of PD-L1-expressing myeloid cells that contributes to establishing an immunosuppressive pancreatic tumor microenvironment.…”

“…The expression of CCL9 in cancer cells is known to be associated with immune evasion via the recruitment of C-C motif chemokine receptor 1 (CCR1)-expressing immunosuppressive myeloid cells into the tumors (10)(11)(12)(13)(14). Hence, we evaluated the expression of CCR1 in intratumoral CD11b + cells using flow cytometry.…”

Comprehensive analysis of prognostic immune‑related genes associated with the tumor microenvironment of pancreatic ductal adenocarcinoma

“…At present, tumor immunotherapy results in marked effects in cancer treatment ( 33 ). The impact of the immune microenvironment on tumor cells has been demonstrated in numerous studies ( 34 , 35 ). Immunotherapy has emerged as an option for pancreatic cancer ( 36 ).…”

The Immune Microenvironment in Pancreatic Cancer

“…They form a long-term existing memory, thereby establishing protection from cancer recurrence [ 149 ]. However, tumors induce a dysfunctional state in CTLs termed exhaustion , which is characterized by an impairment of effector function, reduced survival, and increased expression of inhibitory receptors including the checkpoint inhibitors programmed cell death 1 (PD1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) [ 173 , 174 ]. Immunotherapy of tumors by a checkpoint blockade has led to durable responses in melanoma, non-small cell lung carcinoma, head-and-neck cancer, and urothelial carcinoma [ 174 ].…”