Roles of differently polarized macrophages in the initiation and progressionof pancreatic cancer

Abstract

During development of pancreatic cancer macrophage-mediated inflammatory processes and the formation of cancerous lesions are tightly connected. Based on insight from mouse models we provide an overview on the functions of classically-activated pro-inflammatory and alternatively-activated anti-inflammatory macrophages in the initiation and progression of pancreatic cancer. We highlight their roles in earliest events of tumor initiation such as acinar-to-ductal metaplasia (ADM), organization of the fibrotic lesion microenvironment, and growth of low-grade (LG) lesions. We then discuss their roles as tumor-associated macrophages (TAM) in progression to high-grade (HG) lesions with a cancerous invasive phenotype and an immunosuppressive microenvironment. Another focus is on how targeting these macrophage populations can affect immunosuppression, fibrosis and responses to chemotherapy, and eventually how this knowledge could be used for novel therapy approaches for patients with pancreatic ductal adenocarcinoma (PDA).

Macrophages foster adaptive anti-tumor immunity by ZEB1-dependent cytotoxic T cell chemoattraction

“…We demonstrate that myeloid ZEB1 is dispensable for organogenesis and hematopoiesis, but in TAMs, it modulates the anti-tumor immune response. TAMs are mostly associated with tumor promotion, but also exhibit tumor-suppressive functions (Storz 2023, Malfitano et al 2020. We discovered an important function of ZEB1 in macrophages to limit heterotopic tumor and lung metastatic growth by cytokine-mediated CTL recruitment in syngeneic models of two gastrointestinal tumor entities, without direct noticeable effects on tumor cells.…”

“…Tumorassociated macrophages (TAMs) are one of the most abundant innate immune cell types in the TME (Pinto et al 2019, Guo et al 2022, Falcomata et al 2023. Macrophages/TAMs polarize between "inflammatory" and "alternative" states -the two extreme poles of a broad spectrum of phenotypes which can either have anti-or pro-tumorigenic effects (Mantovani et al 2022, Storz 2023. One major role of TAMs is the recruitment of immune cells such as monocytes, neutrophils and T cells via secreted chemokines (Takeya and Komohara 2016).…”

New Strategies for Macrophage Re-Education in Cancer: An Update

“…Besides CCR2, CCR4 is a receptor expressed on monocytes/macrophages that promotes their migration [ 45 , 46 ]. The CCL2/CCR4 axis plays a role as a chemoattractant of monocytes/macrophages in pancreatic ductal carcinoma (PDA) and in murine pancreatic cancer [ 47 , 48 , 49 ]. Therefore, it is a potential immunological target to suppress TAM formation; in fact, CCR4 blockade improves prognosis in pancreatic cancer [ 48 ].…”

Role of lipid metabolism in hepatocellular carcinoma

“…Macrophages are the innate immunocytes involved in various biological processes, including host defense, homeostasis and disease progression. The surrounding microenvironment induces the polarization of M1 and M2 macrophage phenotypes [ 85 ]. TAMs show similar functions as M2s, as some researchers demonstrate TAMs as a polarized M2 macrophage population [ 86 ].…”