Macrophages in Lung Cancer

Macrophages and Lung Cancer

Lung cancer remains the most common cancer type worldwide and it is the leading cause of cancer death. With its highly complex mutational landscape, treatment strategies against lung cancer have proved largely ineffective. However, with the recent success of immunotherapy trials in lung cancer, there is renewed enthusiasm in targeting the immune component of tumors. Crosstalk between tumor cells and other tumor-associated cells may lead to either inhibition of tumor formation or enhancement of tumor growth and progression. Making up the majority of the immune infiltrate in tumor, macrophages are a key cell type related to cancer and are believed to play an important role in the growth, progression, and metastasis of tumors. Tumor-associated macrophages (TAMs) play an important role in lung cancer initiation and progression. They provide a suitable microenvironment to support growth, immunosuppression, invasion, and therapeutic resistance in lung cancer, primarily by secreting transforming growth factor-beta (TGF-β), interleukin (IL)-10, CC chemokine ligand 18 (CCL18), matrix metalloproteases (MMPs), vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2) and platelet-derived growth factor (PDGF).

Origin of TAMs in Lung Cancer

There is accumulating evidence that has indicated that the majority of TAMs originate from blood monocytes, and tumor-derived chemotactic signals, such as C-C motif chemokine ligand 2 (CCL2), are responsible for recruiting TAMs at tumor sites. Moreover, a small group develops from in situ monocyte-macrophage proliferation and splenic monocytes. However, lung cancer exhibits a high proportion of tissue-resident macrophages, called alveolar macrophages, which are also derived from peripheral blood monocytes. Therefore, the peripheral monocytes and resident mature monocytes significantly contribute to the origin of TAMs in lung cancer.

TAMs: M2-type Macrophages

While the nuclear factor kappa B (NF-κB) pathway is a key regulator of inflammation, TAMs display low expression of NF-κB-dependent cytotoxic mediators and inflammatory cytokines, but higher expression of typical M2 markers, such as arginase-I (Arg-I), scavenger receptor-A (SR-A), mannose receptor (MR), YM1 and found in inflammatory zone 1 (FIZZ1), and MGL2. Previous studies have suggested that TAMs resemble M2 macrophages in vitro and in vivo. Since macrophages are highly plastic cells they may be differentiated into several phenotypes. Polarization is dynamic and affected by the tumor microenvironment (TME). The M2-type macrophages may be reversed to M1-type under certain conditions. Therefore, the dichotomy of M1 and M2 subtypes only partially represents the continuity of polarization, and M1 and M2 markers may be used to distinguish macrophage populations to a certain extent.

Clinical Implications of TAMs in Lung Cancer

Clinical studies have suggested that the density of macrophages, particularly M2 type, is associated with a poor prognosis in almost all human cancer types. However, there are contradictory results with regard to lung cancer. Taken together, the tumor histological type and origin in patients, methodologies applied in counting TAMs, and definition of islet and stroma may explain those different data. Moreover, a recent meta-analysis has reported that M2-type TAMs or M1/M2 polarization in the lung cancer islets or stroma is associated with tumor progression. Therefore, targeting TAMs may be a newer anti-tumor strategy in lung cancer.

Fig.1 Anti-tumor therapies targeted TAMs in lung cancer. (Xu, 2020)

TAM-targeted Therapeutics

TAMs serve an important role in tumor behavior, and thus several therapies targeting TAMs have been employed. 1) Inhibition of macrophages infiltrating the tumor by blockade of CCL2-CCR2 or CSF1-CSF1R, reversing the immunosuppressive status. 2) Blockade of M2-type by interventing the signaling components, which regulate M2-type macrophage polarization, including Toll-like receptors (TLR), STAT6, and NK-κB. 3) Reprogramming TAMs to M1-type by drugs, such as BTH1677, hydroxychloroquine, and celecoxib. Although the strategies above provide enhanced and promising therapeutic effects, there are still a few side effects, including the efficiency of specific drug delivery and nontargeting TAMs. However, evidence has suggested that Nanoparticle-based Drug Delivery is more reliable and effective in targeting macrophage phenotype without off-target activity.

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Reference

1. Xu, F.; et al. Tumor-associated macrophages in lung cancer: Friend or foe?. Molecular Medicine Reports. 2020, 22(5):4107.