Macrophages: The Road Less Traveled, Changing Anticancer Therapy

Abstract

Macrophages are present in all vertebrate tissues and have emerged as multifarious cells with complex roles in development, tissue homeostasis, and disease. Macrophages are a major constituent of the tumor microenvironment, where they either promote or inhibit tumorigenesis and metastasis depending on their state. Successful preclinical strategies to target macrophages for anticancer therapy are now being evaluated in the clinic and provide proof of concept that targeting macrophages may enhance current therapies; however, clinical success has been limited. This review discusses the promise of targeting macrophages for anticancer therapy, yet highlights how much is unknown regarding their ontogeny, regulation, and tissue-specific diversity. Further work might identify subsets of macrophages within different tissues, which could reveal novel therapeutic opportunities for anticancer therapy.

Getting TANned: How the tumor microenvironment drives neutrophil recruitment

“…Functional plasticity is commonly observed in mononuclear leukocytes. Based on their activation status, macrophages, for example, are categorized into the classically activated, proinflammatory M1 type and the alternatively activated, anti‐inflammatory or immunosuppressive M2 type . In the context of tumors, TAMs potentially undergo a transition from an antitumoral (M1) to a protumoral (M2) activation mode that is instructed by the cytokine milieu in the TME .…”

“…TAMs are represented by tumor‐resident macrophages (TRMs) and the ones derived from circulating classical monocytes (CCR2 high ) after extravasation into tissues. Both are TME integral cell types that are well characterized and recognized for their contribution to the establishment and spread of cancer . Although bone marrow is the major source of circulating monocytes, spleen can serve as an extramedullary reservoir of monocytic progenitors and supply monocytes into tumors as detected in tumor‐bearing mice .…”

“…Based on their activation status, macrophages, for example, are categorized into the classically activated, proinflammatory M1 type and the alternatively activated, anti-inflammatory or immunosuppressive M2 type. 3,72 In the context of tumors, TAMs potentially undergo a transition from an antitumoral (M1) to a protumoral (M2) activation mode that is instructed by the cytokine milieu in the TME. 3 Similar to TAMs, in two studies 18,19 involving mouse tumor models, neutrophils with different activation modes have been observed: the tumor-regressive N1 and the tumor-promoting N2 TANs.…”

“…Both are TME integral cell types that are well characterized and recognized for their contribution to the establishment and spread of cancer. 72,125 Although bone marrow is the major source of circulating monocytes, spleen can serve as an extramedullary reservoir of monocytic progenitors and supply monocytes into tumors as detected in tumor-bearing mice. 126,127 Monocyte recruitment into tumors is largely dependent on the CCL2-CCR2 chemokine-receptor axis, 72,128,129 however other factors, including chemokine CCL5 and CSF-1, assist during monocyte migration to the TME.…”

“…72,125 Although bone marrow is the major source of circulating monocytes, spleen can serve as an extramedullary reservoir of monocytic progenitors and supply monocytes into tumors as detected in tumor-bearing mice. 126,127 Monocyte recruitment into tumors is largely dependent on the CCL2-CCR2 chemokine-receptor axis, 72,128,129 however other factors, including chemokine CCL5 and CSF-1, assist during monocyte migration to the TME. 72,128,130 On the other hand, non-classical monocytes (CX3CR1 high ) mostly patrol inside the blood vessel and scavenge tumor elements, thus resisting metastasis.…”