CXCL9-expressing tumor-associated macrophages: new players in the fight against cancer

Abstract

Tumor-associated macrophages (TAMs) are among the main contributors to immune suppression in the tumor microenvironment, however, TAM depletion strategies have yielded little clinical benefit. Here, we discuss the concept that TAMs are also key regulators of anti-PD(L)-1-mediated CD8 T cell-dependent immunity. Emerging data suggest that expression of the chemokine CXCL9 by TAMs regulates the recruitment and positioning of CXCR3-expressing stem-like CD8 T (T_stem) cells that underlie clinical responses to anti-PD(L)-1 treatment. We evaluate clinical and mechanistic studies that establish relationships between CXCL9-expressing TAMs, T_stem and antitumor immunity. Therapies that enhance anti-PD(L)-1 response rates must consider TAM CXCL9 expression. In this perspective, we discuss opportunities to enhance the frequency and function of CXCL9 expressing TAMs and draw on comparative analyzes from infectious disease models to highlight potential functions of these cells beyond T_stem recruitment.

Keywords: CD8-Positive T-Lymphocytes; immunotherapy; macrophages; review.

Figure 1

Scenarios of CXCL9 function in the tumor microenvironment. Expression of chemokine CXCL9 by macrophages within the tumor microenvironment may serve multiple purposes in generating an efficacious immune response to PD-L(1) checkpoint therapy. (A) Newly primed T cells in tumor draining lymph nodes upregulate CXCR3 and may be recruited to sources of CXCL9 in the tumor, allowing for infiltration of non-exhausted effector T cells. (B) CXCL9 secretion by macrophages may position newly primed effector T cells closer to APCs such as classical DCs, which have been shown to be necessary for efficacy of PD-L(1) treatment. (C) As a potential mechanism for maintaining a non-exhausted effector T cell pool, CXCL9 may be used to recruit and position TCF1+ T cells within specialized niches of the TME. APCs, antigen-presenting cells; DCs, dendritic cells; IFN, interferon; PD-L1, programmed death ligand 1; TAM, tumor-associated macrophage; TME, tumor microenvironment.