Myeloid Cells as Targets for Therapy in Solid Tumors

Abstract

It is well established that cancer development ensues based on reciprocal interactions between genomically altered neoplastic cells and diverse populations of recruited "host" cells co-opted to support malignant progression. Among the host cells recruited into tumor microenvironments, several subtypes of myeloid cells, including macrophages, monocytes, dendritic cells, and granulocytes contribute to tumor development by providing tumor-promoting factors as well as a spectrum of molecules that suppress cytotoxic activities of T lymphocytes. Based on compelling preclinical data revealing that inhibition of critical myeloid-based programs leads to tumor suppression, novel immune-based therapies and approaches are now entering the clinic for evaluation. This review discusses mechanisms underlying protumorigenic programming of myeloid cells and discusses how targeting of these has potential to attenuate solid tumor progression via the induction and of mobilization CD8 cytotoxic T cell immunity.

FIGURE 1

Strategies targeting myeloid cell–lymphocyte interactions to promote antitumor immunity. A protumorigenic TME is fostered by signals (dashed arrows) originating from tumor cells and myeloid-lymphocyte interactions. Therapies designed to prevent myeloid cell recruitment from blood (red box; A) to TMEs or inhibit macrophage survival (B) lead to mobilization (C) and proliferation (D) of CD8⁺ T cells, which function to inhibit tumor growth. Inhibition of B cell signaling (E) slows malignant progression via mobilization of antitumor CD8⁺ T cells (F) and through inhibition of myeloid-associated tumor-promoting pathways (G). The antitumor efficacy of these therapies may be amplified when used in combination with chemotherapy/radiation (CTX/RT) therapy (purple box) as compared with monotherapy (gray box). In the absence of tumor-associated macrophages (A, B), CTX/RT-induced release of tumor antigens stimulates DC maturation (H) and trafficking to regional lymph nodes (brown box) where cross-presentation (I) to CD8⁺ T cells occurs. In this context, macrophage depletion (A, B) and/or therapies associated with M2-to-M1 repolarization (J) mobilize granzyme B (K) and interferon-secreting (L) CD8⁺ T cells to TMEs whereupon these cells mount cytolytic attacks on tumor cells. Green arrows indicate propagation of therapy-induced antitumor programs via mechanisms denoted by thick red lines. Thin red lines represent pre-established inhibitory pathways. FcγR indicates Fc γ receptor; GzB, granzyme B; CTX, chemotherapy; RT, radiation therapy; IL-10, interleukin-10; IFN-γ, interferon γ; RONi, receptor tyrosine kinase RON inhibitor; SYKi, spleen tyrosine kinase inhibitor; Btki, Btk inhibitor; CSF-1Ri, CSF-1R inhibitor; PI3Kγ/δi, PI3Kγ/δ inhibitor.