Research ArticleTUMOR IMMUNOLOGY

Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding

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Science Immunology  17 Jul 2020:
Vol. 5, Issue 49, eabc2728
DOI: 10.1126/sciimmunol.abc2728

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Lending PD1 a helping hand

LAG3 is an inhibitory receptor expressed on exhausted T cells that is thought to temper T cell activation by engaging peptide–MHC class II complexes. Here, Andrews et al. have engineered mice expressing a noncleavable form of LAG3 (LAG3NC) that cannot be shed from the cell surface by ADAM family proteases. By generating mouse strains that express LAG3NC ion-distinct T cell types, they found that LAG3 shedding by conventional CD4+ T cells rather than T regulatory cells (Tregs) or CD8+ T cells to be important for driving responsiveness to anti-PD1. Although both CD8+ T cells and Tregs have received considerable attention in the context of immunotherapy, this study highlights the importance of T cell help in promoting antitumor immunity.

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