Tumor-Associated Macrophages in Pancreatic Ductal Adenocarcinoma: Origin, Polarization, Function, and Reprogramming

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy. PDAC is only cured by surgical resection in its early stage, but there remains a relatively high possibility of recurrence. The development of PDAC is closely associated with the tumor microenvironment. Tumor-associated macrophages (TAMs) are one of the most abundant immune cell populations in the pancreatic tumor stroma. TAMs are inclined to M2 deviation in the tumor microenvironment, which promotes and supports tumor behaviors, including tumorigenesis, immune escape, metastasis, and chemotherapeutic resistance. Herein, we comprehensively reviewed the latest researches on the origin, polarization, functions, and reprogramming of TAMs in PDAC.

Keywords: origin; pancreatic ductal adenocarcinoma; polarization; reprogramming; tumor-associated macrophages.

FIGURE 1

The roles of tumor-associated macrophages (TAMs) in pancreatic ductal adenocarcinoma (PDAC). (A) TAMs can produce more inflammatory stimulations to promote acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) from normal tissue under KRAS mutation, thus accelerating the maturation of PDAC. (B) TAMs induce immunosuppression in the PDAC microenvironment via multiple ways, including releasing immunosuppressive cytokines, inhibiting the activity of tumor-infiltrating immune cells, and facilitating other inhibitory cells. (C) TAMs can promote the early metastasis of PDAC through proangiogenesis, promoting epithelial–mesenchymal transition (EMT), degrading the exocellular matrix, and sustaining the survival and growth of metastasis sites. (D) TAMs mediate chemotherapy resistance in an indirect and direct way. They create an adverse environment by remodeling desmoplastic stroma and suppressing immune response against the efficacy of chemotherapy. Meanwhile, they have a system of adaptation to reduce the attack of chemotherapeutic agents like releasing pyrimidine species to molecularly compete with gemcitabine, upregulating cytidine deaminase of tumor cells to decrease sensitivity to chemotherapy, and restraining the expansion of tumor cell death by timely eliminating apoptotic cells and factors.

FIGURE 2

The origin and polarization of TAMs in PDAC. TAMs originated from the self-renewal of yolk sac progenitors and the recruitment of bone marrow-derived monocytes, and they are gradually differentiated into TAMs under tumor circumstance. Subject to tumor microenvironment, TAMs are predominantly orchestrated toward the M2 phenotype, which is protumoral, and there is a transformation between antitumoral M1 and M2. Accordingly, the increase of M2 infiltration contributes to the malignant growth of PDAC.

FIGURE 3

Current strategies to reprogram TAMs in PDAC. Induction from M2 to M1 is a fundamental concept for PDAC therapy, and it can be summarized into three approaches: activating TAMs to M1, inhibiting TAMs to M2, and depleting the monocyte–macrophage system. Immune promoters can be applied to activate the immune system to switch on M1 such as some pro-inflammatory cytokines, TLR agonists, and CD40 agonists. Anti-CSF-1, anti-Tie2, and anti-CD47 can all repress TAMs toward M2. Beyond these, inhibiting intercellular signal molecules can target and block M2 deviation, thus reviving antitumor activity.