VEGF-A drives TOX-dependent T cell exhaustion in anti–PD-1–resistant microsatellite stable colorectal cancers

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Science Immunology  08 Nov 2019:
Vol. 4, Issue 41, eaay0555
DOI: 10.1126/sciimmunol.aay0555

Trawling for drivers of T cell exhaustion

Although checkpoint blockade has markedly changed the landscape of cancer therapeutics, not all tumors are responsive to immunotherapy. Here, Kim et al. studied T cell exhaustion in two distinct types of colorectal cancers (CRCs), microsatellite instability–high (MSI) CRCs that are responsive to PD-1 blockade and microsatellite stable (MSS) CRCs that are resistant to PD-1 centric therapies. Although tumor-infiltrating T cells in both types of CRCs were exhausted, they report T cell exhaustion in MSS but not MSI CRCs to be driven by VEGF-A. Using mouse models, they demonstrate that combined blockade of both PD-1 and VEGF-A makes MSS CRCs sensitive to PD-1 blockade. Their study highlights how in-depth characterization of checkpoint-resistant tumors can lead to identification of pathways to sensitize them to immunotherapy.

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