To assess whether LAG3 shedding by metalloproteases ADAM10 and ADAM17 plays a role in responsiveness to PD-1 blockade, Andrews et al. evaluated the effect of anti-PD-1 in mice expressing a non-cleavable form of LAG3 (LAG3NC) in T cells. In four tumor models, mice expressing LAG3NC were resistant to PD-1 inhibition due to selective loss and decreased function of conventional intratumoral CD4+Foxp3- T cells, resulting in failure to provide CD8+ T cell help. A high LAG3/low ADAM10 ratio correlated with poor prognosis and increased disease progression in patients with several tumor types (HNSCC, melanoma, and skin).
Contributed by Katherine Turner
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.