The roles of tissue resident macrophages in health and cancer

Abstract

As integral components of the immune microenvironment, tissue resident macrophages (TRMs) represent a self-renewing and long-lived cell population that plays crucial roles in maintaining homeostasis, promoting tissue remodeling after damage, defending against inflammation and even orchestrating cancer progression. However, the exact functions and roles of TRMs in cancer are not yet well understood. TRMs exhibit either pro-tumorigenic or anti-tumorigenic effects by engaging in phagocytosis and secreting diverse cytokines, chemokines, and growth factors to modulate the adaptive immune system. The life-span, turnover kinetics and monocyte replenishment of TRMs vary among different organs, adding to the complexity and controversial findings in TRMs studies. Considering the complexity of tissue associated macrophage origin, macrophages targeting strategy of each ontogeny should be carefully evaluated. Consequently, acquiring a comprehensive understanding of TRMs' origin, function, homeostasis, characteristics, and their roles in cancer for each specific organ holds significant research value. In this review, we aim to provide an outline of homeostasis and characteristics of resident macrophages in the lung, liver, brain, skin and intestinal, as well as their roles in modulating primary and metastatic cancer, which may inform and serve the future design of targeted therapies.

Keywords: Bone-marrow derived macrophages; Cancer; Homeostasis; Monocytes; Tissue resident macrophages.

Fig. 1

The identity of TRMs is determined by their specific niche of residence. TRMs in different tissues originate from the embryo and rely on distinct niche signals and transcription factors to facilitate their differentiation, survival and self-maintenance. Additionally, TRMs in the lung, liver, brain, skin, and intestine secrete various cytokines and exhibit distinct markers. These factors collectively define the specific identity of TRMs

Fig. 2

Dynamic crosstalk between pro- and antitumorigenic alveolar macrophages (AMs) and tumor cells in primary and metastatic cancers. In primary tumors, AMs expressing P16 and CXCR1 suppress CTL response and promoting the progression of lung tumor via the ROS, BACH1, PDLIM2 and STAT3 signaling pathway; Upregulation of INHBA expression in AMs leads to the secretion of activin A, which inhibits the proliferation of lung cancer cells. Additionally, AMs-derived extracellular vesicles containing SOCS3 suppresses STAT3 activation in cancer cells leading to inhibits the proliferation and survival of lung adenocarcinoma cells. Upregulation of pro-inflammatory genes, such as IL-12β, IL-1α, and IL-1β, and also anti-inflammatory genes, including Smad3 of the TGF-β signaling pathway, and downregulation of Smad7. During cancer metastasis, AMs are recruited from MO-MDSCs through the CXCL10-CXCR3 and TLR4-CCL12 axis, and contributing to the metastatic progression through the Wnt/β-catenin/TNF-α axis

Fig. 3

Dynamic interaction between pro- and antitumorigenic Kupffer cells (KCs) and tumor cells in primary and metastatic cancer. In primary tumors, KCs inhibit the anti-tumor response by activating signaling pathways involving PD-L1/PD-1 and galectin-9/TIM-3 in T cells. Stimulation from cancer cells leads to an increase in TREM-1 expression in KCs, promoting the progression of hepatocellular carcinoma (HCC). TREM-1 deficiency results in the reduced release of IL-1β, IL-6, CCL2, and CXCL10 by KCs, thereby suppressing HCC growth. ROS and TNF produced by KCs contribute to tumor cell proliferation. Constructed MAFB- and MAF-targeting dual sgRNA CRISPR/CasΦ vector in KCs achieved therapeutic effects. During cancer metastasis, KCs was found to decrease tumor growth by altering the expression of INOS and VEGF in cancer cells. Conversely, KCs increased tumor growth through decreased infiltration of T cells and upregulation of COX-2 expression

Fig. 4

Dynamic interplay between pro- and antitumorigenic microglia and tumor cells in primary and metastatic cancers. In primary tumors, microglia enhance the proliferation and migration of cancer cells in both in vitro and in vivo settings by releasing TGF-β, EGF, and STI1. Cancer cells induce microglia to secrete and release IL-6 through the CCL2/CCR2 axis, thereby promoting glioma invasion。During cancer metastasis, tumor cells stimulate the JAK2/STAT3 signaling pathway in microglia by secreting IL-6 and promote tumor cell migration through the secretion of ANXA1, which reduces microglial migration and activates the STAT3. Elevated expression of TGF-β in microglia fosters tolerance towards cancer cells by anti-tumor CTL. CpG-C, inhibits brain metastasis by activating microglia, while the CD47-SIRPα axis acts as a crucial innate immune checkpoint suppressing phagocytic activity in myeloid cells

Fig. 5

Langerhans cells (LCs) exhibit anti-tumor effects. LCs induce proliferation of T cells and enhance the production of IFN-γ. The potency of LCs in T cell response is further enhanced through activation with TLR-3. PAK1 expressed on LCs regulates the number of epidermal stem cells, thereby exerting inhibitory effects on tumor proliferation. CD207 and a glycomimetic Langerin ligand liposomes 22 can serve as transcutaneous cancer vaccine agents via inducing protective T cell immunity

Fig. 6

Intestinal resident macrophages facilitate tumor cell invasion. The transcription factor C-MYC regulates the expression of pro-tumoral genes, such as VEGF, HIF-1α and TGF-β in Tumor-associated macrophages (TAMs), which are characterized by the expression of pattern recognition receptors CD163 and MP, as well as the secretion of cytokines IL-10 and TGF-β, as well as chemokines including CCL17, CCL22 and CCL24. Tumor cells produce lactic acid through the mediation of HIF-1α, which induces VEGF and arginase-1 expression in intestinal resident macrophages. Cancer cells secrete IL-34, promoting the polarization of monocyte towards M2 macrophages, thereby further enhancing tumor proliferation and metastasis. TAMs enhance tumor migration and invasion by the ERK signaling pathway, secreting IL-6, and this effect is mediated via the JAK2/STAT3/FoxQ1 axis