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

LAG3 shedding from conventional CD4+ T cells drives responsiveness to anti-PD1 immunotherapy (see the related Focus by Seidel and Bengsch). Lending PD1 a helping hand LAG3 is an inhibitory receptor expressed on exhausted T cells that is thought to temper T cell activation by engaging peptide–MHC class II complexes. Here, Andrews et al. have engineered mice expressing a noncleavable form of LAG3 (LAG3NC) that cannot be shed from the cell surface by ADAM family proteases. By generating mouse strains that express LAG3NC ion-distinct T cell types, they found that LAG3 shedding by conventional CD4+ T cells rather than T regulatory cells (Tregs) or CD8+ T cells to be important for driving responsiveness to anti-PD1. Although both CD8+ T cells and Tregs have received considerable attention in the context of immunotherapy, this study highlights the importance of T cell help in promoting antitumor immunity. 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.