Editors' ChoiceCancer Immunotherapy

CAFs complicate immunotherapy

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Sci. Signal.  28 Nov 2017:
Vol. 10, Issue 507, eaar5583
DOI: 10.1126/scisignal.aar5583

Anti-CSF1R immunotherapy effectively inhibits one suppressive immune cell type but unleashes another through cancer-associated fibroblasts.

Our understanding of cancer development has progressed from a tumor-centric view to one of a highly complex, cross-talking, and ever-expanding multicellular pathology. Therapeutic strategies are starting to evolve likewise. Immunotherapy, for example, aims to block immunosuppressive signals emanating from tumors and certain immune cell populations to enhance the activity of cytotoxic and effector T cells. This strategy was so promising that clinical studies were swiftly initiated; however, many trials have failed to show the anticipated benefit in patients. Kumar et al. discovered one potential reason why agents that block the cytokine receptor CSF1R ultimately fail to stimulate antitumor immunity (see also the preview by Greten). CSF1 is secreted by tumors and promotes the differentiation of hematopoietic stem cells to macrophages. Hence, as expected, CSF1R blockade with the small-molecule inhibitor JNJ-40346527 decreased the number of tumor-associated macrophages in mouse models of various tumors. However, it also unexpectedly increased the production and secretion of the chemokine CXCL1 by cancer-associated fibroblasts (CAFs), which stimulated the recruitment and accumulation of polymorphonuclear myeloid–derived suppressor cells (PMN-MDSCs) in the tumor microenvironment. CAFs also have CSF1 receptors; CSF1 promoted histone deacetylase–mediated suppression of Cxcl1 expression in CAFs. Combining the CSF1R inhibitor with an inhibitor of the CXCL1 receptor (CXCR2) reduced the numbers of both TAMs and PMN-MDSCs in the tumor microenvironment and substantially reduced tumor growth in mice. The addition of an immune cell checkpoint blockade (anti-PD1) prevented tumor growth for over a month. These findings exemplify how complex and interconnected the tumor microenvironment is and why adequate preclinical testing is necessary to grasp the extended actions and indirect consequences of so-called targeted therapeutics to develop the most effective strategies for patients.

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