PTEN loss confers resistance to anti-PD-1 therapy in nonsmall cell lung cancer by increasing tumor infiltration of regulatory T cells
Immunotherapy resistance in non-small cell lung cancer (NSCLC) may be mediated by an immunosuppressive microenvironment, which can be shaped by the mutational landscape of the tumor. Here, we observed genetic alterations in the PTEN/PI3K/AKT/mTOR pathway and/or loss of PTEN expression in >25% NSCLC patients, with higher frequency in lung squamous carcinomas (LUSCs). Patients with PTEN-low tumors had higher levels of PD-L1 and PD-L2 and showed worse progression-free survival when treated with immunotherapy. Development of a Ptennull LUSC mouse model revealed that tumors with PTEN loss were refractory to antiPD-1, highly metastatic and fibrotic, and secreted TGF-ß/CXCL10 to promote conversion of CD4+ lymphocytes into regulatory T cells (Tregs). Human and mouse PTEN-low tumors were enriched in Tregs and expressed higher levels of immunosuppressive genes. Importantly, treatment of mice bearing Pten-null tumors with TLR agonists and anti-TGF-ß antibody aimed to alter this immunosuppressive microenvironment led to tumor rejection and immunological memory in 100% of mice. These results demonstrate that lack of PTEN causes immunotherapy resistance in LUSC by establishing an immunosuppressive tumor microenvironment that can be reversed therapeutically. Overall design: We generated a PTEN mutant version of the murin lung squamous carcinoma UNSCC680 cells using CRISPR-Cas9 technology. We performed RNAseq from in vitro cultured EVGFP control cells and PTEN mutant cells, at a single time-point. Comparative gene-expression profiling of RNAseq between EVGFP (Control) and PTEN null cells.