Editors' ChoiceCancer Immunology

Enhancing tumor infiltration

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Science Signaling  13 Jul 2021:
Vol. 14, Issue 691, eabl3733
DOI: 10.1126/scisignal.abl3733

Targeting a chemokine receptor inhibitor enhances the trafficking of antitumor T cells into tumors.

Patients with tumors infiltrated with antitumor T helper 1 (TH1) cells and cytotoxic T cells (CTLs) have a better prognosis than those with tumors infiltrated with immunosuppressive cells (see commentary by Fercoq and Carlin). Huang et al. showed that breast cancer patients with greater numbers of tumor-infiltrating TH1 cells and CTLs had longer disease-free survival than did patients with smaller numbers of such cells in their tumors, despite the similar numbers of these cells in their peripheral blood. Tumors that were highly infiltrated and tumors that were not well-infiltrated had similar amounts of T cell–recruiting chemokines and chemokine receptors on TH1 cells and CTLs. Compared to peripheral blood TH1 cells and CTLs from healthy donors, those from breast cancer patients had increased expression of RGS1, a GTPase-activating protein that inhibits chemokine receptor signaling. In vitro assays showed that knockdown of RGS1 enhanced the migration of TH1 cells and CTLs to conditioned medium from primary tumors. Coimmunoprecipitation studies showed that RGS1 bound to the chemokine receptors CXCR3, CCR4, and CXCR4 in TH1 cells and CTLs. Knockdown of RGS1 in these cells led to increased Ca2+ mobilization and signaling by the kinases ERK and Akt in response to the CXCR4 ligand CXCL12. Signaling by the cytokine interferon-γ (IFN-γ) and its downstream effector STAT1 increased the expression of RGS1 in T cells. Blocking STAT1 signaling in TH1 cells and CTLs enhanced their migration toward CXCL12. Finally, adoptively transferred, RGS1-deficient, tumor-specific CTLs showed increased tumor infiltration in mice compared to that of RGS1-replete cells, which led to reduced tumor growth and increased survival. Together, these data suggest that targeting RGS1 in antitumor T cells may represent a strategy to enhance tumor infiltration and immunotherapy.

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