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

SIMPLE SUMMARY: Current studies aim to target tumor-associated macrophages (TAMs) to alleviate immunosuppression and inhibit tumor growth. However, the specific mechanisms that drive TAMs to impede T cell migration into and within tumors are still unclear. Here, we found that after pancreatic ductal adenocarcinoma (PDAC)-bearing mice were treated with clodronate liposomes, the numbers of BrdU-incorporated and Ki-67(+)-proliferating macrophages were reduced, which might be maintained by local proliferation. Clodronate liposomes treatment could alter the macrophages that foster CD8(+) T cell infiltration, promote CD8(+) T cell spatial redistribution in tumors, and suppress PDAC growth. This study suggests that depletion of macrophages may increase CD8(+) T cell infiltration and promote CD8(+) T cell spatial redistribution in tumors, contributing to the antitumor effect. 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.