In:
Science Immunology, American Association for the Advancement of Science (AAAS), Vol. 5, No. 49 ( 2020-07-03)
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 (LAG3 NC ) are resistant to PD1 blockade and fail to mount an effective antitumor immune response. Expression of LAG3 NC intrinsically perturbs CD4 + T conventional cells (T convs ), 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 + T convs 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.
Type of Medium:
Online Resource
ISSN:
2470-9468
DOI:
10.1126/sciimmunol.abc2728
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2020