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 (LAG3(NC)) are resistant to PD1 blockade and fail to mount an effective antitumor immune response. Expression of LAG3NC 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 resist-ance mechanism with a substantive effect on patient responsiveness to immunotherapy.