Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding
Name
nihms-1641289.pdf
Description
Accepted version
Size
2.09 MB
Format
Adobe PDF
Checksum (MD5)
1951a0a18558b033928e1dd89965e79d
Author(s)
Andrews, Lawrence P
Somasundaram, Ashwin
Moskovitz, Jessica M
Szymczak-Workman, Andrea L
Liu, Chang
Cillo, Anthony R
Lin, Huang
Normolle, Daniel P
Moynihan, Kelly Dare
Taniuchi, Ichiro
Date Issued
2020
Journal
Science Immunology
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Andrews, Lawrence P, Somasundaram, Ashwin, Moskovitz, Jessica M, Szymczak-Workman, Andrea L, Liu, Chang et al. 2020. "Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding." Science Immunology, 5 (49).
Version
Author's final manuscript
Abstract
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works 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.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1126/SCIIMMUNOL.ABC2728
