Editors' ChoiceCancer

A killer sidekick for antitumor T cells

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Science Translational Medicine  13 Feb 2019:
Vol. 11, Issue 479, eaaw5325
DOI: 10.1126/scitranslmed.aaw5325

Abstract

Engineered NK cells kill myeloid-derived suppressor cells to aid CAR-T cell antitumor responses.

Myeloid derived suppressor cells (MDSCs) are inhibitory cells that populate the tumor microenvironment (TME) and impair T cell–mediated antitumor responses. These cells limit the efficacy of chimeric antigen receptor (CAR) T cell–based immunotherapy, particularly in solid tumors. In a recent report, Parihar et al. describe a strategy to eliminate MDSC from the TME by means of engineered natural killer (NK) cells and show that these cells can improve treatment with CAR-T cells in a preclinical solid tumor model.

To target MDSCs, the researchers designed a chimeric receptor by fusing the NK receptor NKG2D to the ζ-chain of the T cell receptor. This chimeric receptor allows ligand recognition on MDSCs and tumor cells but is balanced by inhibitory receptors on NK cells to prevent targeting of healthy cells. The authors showed that chimeric NK cells killed NKG2D ligand–expressing tumor cells and MDSCs, and resisted suppression by inhibitory factors found in the TME. In an immunodeficient murine model of a solid tumor xenograft infiltrated by human MDSCs, chimeric NK cells reduced MDSC numbers and impaired tumor growth. Although treating this xenograft model with CAR-T cells alone could not stop tumor growth due to MDSC inhibition, pretreating with chimeric NK cells increased infiltration of CAR-T cells into the tumor, improving CAR-T cell treatment efficacy.

These findings suggest a creative approach to reduce MDSCs and improve T cell–based immunotherapy for solid tumors. Additional research in other models and careful examination of potential toxicity from targeting NKG2D ligand–expressing tissues is still needed. Nonetheless, chimeric NKs may represent a broadly applicable strategy to improve CAR-T therapy and other T cell–based cancer treatments.

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