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Inhibitory receptors control immune responses preventing exacerbated T cell activation and the onset of autoimmunity; however, they also limit antitumor immunity. Enhanced co-expression of PD1 and LAG3 phenotypically mark functionally exhausted tumor-specific T cells, with dual PD1/LAG3 blockade synergistically limiting tumor growth in murine models. Like PD1, LAG3 expression is induced on activated T cells to negatively regulate T cell activation and proliferation and LAG3 is also required for maximal regulatory T (Treg) cell function. However, LAG3 expression and function is itself regulated by cell surface cleavage of the transmembrane domain connecting peptide by ADAM10 and ADAM17 metalloproteinase-disintegrins. This releases soluble LAG3, of which no biological function has been found to date. To investigate the impact of LAG3 cleavage on T cells within tumors, a non-cleavable LAG3 mouse (LAG3.NC) was generated in which exons 7 and 8 of Lag3, including the connecting peptide, is deleted in Cre-expressing cells. These exons are replaced and modified so that the connecting peptide is absent preventing LAG3 cleavage. LAG3.NC CD4Cre mice (with non-cleavable LAG3 expressed on all CD8+ and CD4+ T cells, including Tregs) and LAG3.NC E8ICre mice (restricted to CD8+ T cells only) exhibit enhanced expression of LAG3 on the respective T cell subsets in B16-F10 or MC38 tumors, co-expressing with PD1. Despite increased LAG3 expression, no difference in B16-F10 or MC38 tumor growth was observed in either LAG3.NC CD4Cre or LAG3.NC E8ICre mice compared with wild-type littermates. Upon therapeutic administration of anti-PD1 antibody (clone G4), MC38 tumor-bearing wild-type mice show significant tumor regression and 40% become tumor-free resulting in long-term survival. LAG3.NC CD4Cre mice were resistant to anti-PD1 therapy and succumb to tumor growth. However, anti-PD1 mediated tumor regression and long-term survival in LAG3.NC E8ICre mice. Analysis of re-stimulated CD8+ TILs isolated from LAG3.NC CD4Cre mice did not show enhanced IFN-gamma and TNF-alpha production following anti-PD1 therapy, which was observed with LAG3.NC E8ICre mice or wild-type littermates. Moreover, reduced proliferation was observed for all T cell subsets in LAG3.NC CD4Cre mice compared with LAG3.NC E8ICre and wild-type littermates following anti-PD1 treatment. As LAG3.NC CD4Cre, but not LAG3.NC E8ICre mice, are resistant to the favorable antitumor immune effects induced by anti-PD1, this suggests that enhanced LAG3 expression on CD4+ T cells or Tregs may act as a barrier to effective anti-PD1 immunotherapy. LAG3.NC mice crossed with Cre that restricts non-cleavable LAG3 to Tregs (Foxp3yfpiCre) or CD4+ T cells (ThPOKCre) are currently under analysis.