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

Mechanisms of resistance to cancer immunotherapy remain poorly understood. Lymphocyte activation gene-3 (LAG3) signaling is regulated by a disintegrin and metalloprotease domain-containing protein-10 (ADAM10)- and ADAM17-mediated cell surface shedding. Here, we show that mice expressing a metalloprotease-resistant, noncleavable LAG3 mutant (LAG3NC) are resistant to PD1 blockade and fail to mount an effective antitumor immune response. Expression of LAG3NC intrinsically perturbs CD4+ T conventional cells (Tconvs), limiting their capacity to provide CD8+ T cell help. Furthermore, the translational relevance for these observations is highlighted with an inverse correlation between high LAG3 and low ADAM10 expression on CD4+ Tconvs in the peripheral blood of patients with head and neck squamous cell carcinoma, which corresponded with poor prognosis. This correlation was also observed in a cohort of patients with skin cancers and was associated with increased disease progression after standard-of-care immunotherapy. These data suggest that subtle changes in LAG3 inhibitory receptor signaling can act as a resistance mechanism with a substantive effect on patient responsiveness to immunotherapy. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Citation

Lawrence P Andrews, Ashwin Somasundaram, Jessica M Moskovitz, Andrea L Szymczak-Workman, Chang Liu, Anthony R Cillo, Huang Lin, Daniel P Normolle, Kelly D Moynihan, Ichiro Taniuchi, Darrell J Irvine, John M Kirkwood, Evan J Lipson, Robert L Ferris, Tullia C Bruno, Creg J Workman, Dario A A Vignali. Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding. Science immunology. 2020 Jul 17;5(49)

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PMID: 32680952

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