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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article numbereabc2728
JournalScience Immunology
Volume5
Issue number49
DOIs
StatePublished - Jul 2020

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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