Depletion of tumor-associated macrophages switches the epigenetic profile of pancreatic cancer infiltrating T cells and restores their anti-tumor phenotype

Abstract

Pancreatic Ductal Adenocarcinoma (PDA) is characterized by a complex tumor microenvironment that supports its progression, aggressiveness and resistance to therapies. The delicate interplay between cancer and immune cells creates the conditions for PDA development, particularly due to the functional suppression of T cell anti-tumor effector activity. However, some of the mechanisms involved in this process are still poorly understood. In this study, we analyze whether the functional and epigenetic profile of T cells that infiltrate PDA is modulated by the microenvironment, and in particular by tumor-associated macrophages (TAMs). CD4 and CD8 T cells obtained from mice orthotopically injected with syngeneic PDA cells, and untreated or treated with Trabectedin, a cytotoxic drug that specifically targets TAMs, were sorted and analyzed by flow cytometry and characterized for their epigenetic profile. Assessment of cytokine production and the epigenetic profile of genes coding for IL10, T-bet and PD1 revealed that T cells that infiltrated PDA displayed activated promoter and repressed activity, in agreement with their regulatory phenotype (IL10/IFNγ, PD1). By contrast, in Trabectedin-treated mice, PDA-infiltrating T cells displayed repressed and and activated promoter activity, in accordance with their anti-tumor effector phenotype (IL10/IFNγ), indicating a key role of TAMs in orchestrating functions of PDA-infiltrating T cells by modulating their epigenetic profile towards a pro-tumoral phenotype. These results suggest the targeting of TAMs as an efficient strategy to obtain an appropriate T cell anti-tumor immune response and open new potential combinations for PDA treatment.

Specific Effects of Trabectedin and Lurbinectedin on Human Macrophage Function and Fate—Novel Insights

“…Macrophages have been considered as key components for the survival of many tumors [ 31 , 37 , 38 , 39 ]. These tumor-associated macrophages (hTAMs) are educated by cancer cells and the stromal microenvironment to block the action of the adaptive immune system to fight and prevent tumor growth [ 38 , 40 , 41 , 42 , 43 ]. Not only do hTAMs contribute to avoiding immunosuppression, but they also participate in other tumor-supporting functions, such as neovascularization and the spread of tumor cells.…”

“…One additional observation was the decrease in the cell surface levels of PD-L1, which might contribute to reinforce the immune surveillance action of the adaptive immune system against tumor cells [ 43 , 60 ].…”

Current Strategies to Target Tumor-Associated-Macrophages to Improve Anti-Tumor Immune Responses

“…A preclinical study recently showed in a chronic lymphocytic leukemia mouse model that trabectedin induced leukemic cell death and depletion of the immuno-suppressive myeloid-derived suppressor cells and TAMs [102]. Anti-tumor activity by trabectedin, through effects on TAMs, has also been reported in pre-clinical models of skeletal metastatic prostate tumor, melanoma, and pancreatic tumor [103][104][105].…”

Trial watch: chemotherapy-induced immunogenic cell death in immuno-oncology

“…by activating the expression of NK cellactivatory ligands). 15,141,[334][335][336][337][338][339] Finally, most immunooncology trials do not select chemotherapeutics based on their immunostimulatory potential (which in many cases does not manifest at clinically employed dose regimens), but rather based on their use a standard-of-care for selected indications. At least in some cases, such a design precludes the activation of clinically meaningful anticancer immune responses and hence limits the clinical benefit of combinatorial regimens.…”