Targeting Proliferating Tumor-Infiltrating Macrophages Facilitates Spatial Redistribution of CD8+ T Cells in Pancreatic Cancer

Abstract

Tumor-associated macrophages (TAMs) play crucial roles in cancer progression, but the contributions and regulation of different macrophage subpopulations remain unclear. Here, we report a high level of TAM infiltration in human and mouse pancreatic ductal adenocarcinoma (PDAC) models and that the targeting of proliferating F4/80+ macrophages facilitated cytotoxic CD8+ T-cell-dependent antitumor immune responses. A well-defined KPC-derived PDAC cell line and the murine Panc02 PDAC cell line were used. Treatment of PDAC-bearing mice with clodronate liposomes, an agent that chemically depletes macrophages, did not impact macrophage subpopulations in the local tumor microenvironment (TME). However, further investigation using both BrdU and Ki67 to evaluate proliferating cells showed that clodronate liposomes treatment reduced proliferating macrophages in the KPC and Panc02 models. We further evaluated the distance between CD8+ T cells and PanCK+ tumor cells, and clodronate liposomes treatment significantly increased the number of CD8+ T cells in close proximity (<30 µm) to PanCK+ PDAC cells, with increased numbers of tumor-infiltrating IFN-γ+CD8+ T cells. This study suggests that targeting proliferating tumor-infiltrating macrophages may increase CD8+ cytotoxic lymphocyte (CTL) infiltration and facilitate the spatial redistribution of CD8+ T cells in tumors, contributing to the antitumor effect.

Histone Deacetylase Inhibitors Restore Cancer Cell Sensitivity towards T Lymphocytes Mediated Cytotoxicity in Pancreatic Cancer

“…Despite the presence of many immune cells in the tumour microenvironment (TME), pancreatic cancer patients are frequently associated with immune dysfunction, where the TME is highly immunosuppressive, hence restricting the activation and effector function of T cells, particularly the CTL [ 6 , 7 ]. CTL is the primarily mediators of antitumour immunity by inducing tumour cells lysis [ 36 ]. Hiraoka and co-workers highlighted that infiltration of CTL was marked in low-grade premalignant lesions but diminished during the progression of pancreatic intraepithelial neoplasias (PanINs) and intraductal papillary-mucinous neoplasms (IPMNs) [ 37 ].…”

Engineering extracellular vesicles derived from macrophages for tumor therapy: a review

“…In treatment process of pancreatic cancer, clodronate liposomes could foster CD8 + T cell infiltration to alter macrophages and suppress tumor growth. 53 (5) MAb targeted-therapy, a promising cancer treatment option for TAMs, is engage in antibody-dependent cytotoxicity/cell phagocytosis through the binding of their cell surface expression receptors to the antibody Fc fragment. 54 In mice, FcgRI, FcgRIIa and FcgRIIIa are activated receptors, while FcgRIIb is an inhibitory receptor.…”

“…In treatment process of pancreatic cancer, clodronate liposomes could foster CD8 + T cell infiltration to alter macrophages and suppress tumor growth. 53…”

Role of tumor-associated macrophages in common digestive system malignant tumors

“…In pancreatic ductal adenocarcinoma (PDAC), receptor-interacting serine/threonine protein kinase (RIP)1 inhibition in TAMs resulted in CTL activation and T helper (Th) cell differentiation toward a mixed Th1/Th17 phenotype[ 40 ]. By targeting proliferating tumor-infiltrating macrophages, the infiltration of CD8 + CTL and the spatial redistribution of CD8 + T cells within tumors could be escalated[ 41 ]. TAMs are critical regulators in orchestrating epigenetic profile of PDAC-infiltrating T cells towards a protumoral phenotype[ 42 ].…”