Editors' ChoiceCancer

TAMpering with TIME

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Science Translational Medicine  04 Sep 2019:
Vol. 11, Issue 508, eaaz0308
DOI: 10.1126/scitranslmed.aaz0308


CXCR2 inhibition reprograms tumor-associated macrophages to suppress prostate cancer progression.

The human immune system is naturally antitumor, and the premise of immune checkpoint blockade in cancer therapy is to relieve the constraints on cytotoxic T lymphocytes so they can kill tumor cells. Prostate cancers are notoriously resistant to many immunotherapies, which is due in part to their anti-inflammatory phenotype, in which populations of T cells are excluded from the tumor niche. Thus, strategies to promote tumor inflammation require understanding the anti-inflammatory properties of the tumor cells and the contents of the tumor immune microenvironment (TIME) that prevent an effective immune response. Among the predominant immune cell types residing in most prostate tumors are tumor-associated macrophages (TAMs).

TAMs can switch from being proinflammatory and antitumorigenic (secreting cytokines to recruit T cells) to being anti-inflammatory and protumorigenic (expressing transforming growth factor–β or secreting angiogenic vascular endothelial growth factors). Clinically, approaches to eliminate protumorigenic TAMs from tumors also resulted in the suppression of antitumorigenic TAMs, so attention has turned to finding ways to reprogram, or re-educate, TAMs, exploiting their plasticity.

Di Mitri et al. investigated the programming of TAMs in a genetically engineered mouse model of metastatic prostate cancer in which both of the tumor suppressors Pten and Trp53 were deleted. The authors observed an increase in TAM infiltration with tumor progression, and by profiling cytokines on an array, found up-regulation of C-X-C motif chemokine ligand 2 (CXCL2), a ligand of the C-X-C motif chemokine receptor 2 (CXCR2). After isolating macrophages from mouse bone marrow and exposing them to CXCL2, they observed a shift in macrophage gene expression such that anti-inflammatory genes were upregulated and proinflammatory genes were downregulated. The authors then treated Pten/Trp53-null mice with an antagonist of CXCR2, AZD5069. Compared with control mice, the treated mice had smaller tumors, and when the tumors were dissociated, the authors recovered TAMs that had upregulated several proinflammatory and antitumorigenic genes including tumor necrosis factor–α, which bound to tumor cells and induced apoptosis.

Clinical trials of the CXCR2 inhibitor AZD5069 have already been completed in patients with pulmonary diseases such as asthma and bronchiectasis, but it is still unknown whether TAMs of human prostate tumors would be re-educated as they were in the mouse model. To answer this question, the authors have designed a trial (NCT03177187) to treat metastatic prostate cancer patients with AZD5069 in conjunction with other treatments. Analysis of immune cell populations in these patients may reveal whether TAMs re-education is an effective immunotherapy in prostate cancer.

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