PTEN Loss Confers Resistance to Anti-PD-1 Therapy in Non-Small 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% of patients with NSCLC, with higher frequency in lung squamous carcinomas (LUSC). 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 Pten-null LUSC mouse model revealed that tumors with PTEN loss were refractory to antiprogrammed cell death protein 1 (anti-PD-1), highly metastatic and fibrotic, and secreted TGF(3/CXCL10 to promote conversion of CD4 thorn lymphocytes into regulatory T cells (Treg). 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(3 antibody aimed to alter this immunosuppressive microenvironment and led to tumor rejection and immunologic memory in 100% of mice. These results demonstrate that lack of PTEN causes immuno-therapy resistance in LUSCs by establishing an immunosuppres-sive tumor microenvironment that can be reversed therapeutically.Significance: PTEN loss leads to the development of an immu-nosuppressive microenvironment in lung cancer that confers resis-tance to anti-PD-1 therapy, which can be overcome by targeting PTEN loss-mediated immunosuppression.

Automated summary

Immunotherapy resistance in non-small cell lung cancer (NSCLC) can be attributed to an immunosuppressive microenvironment created by genetic alterations in the PTEN/PI3K/AKT/mTOR pathway and/or loss of PTEN expression. PTEN-low tumors are associated with higher levels of immune checkpoint proteins and poorer response to immunotherapy. Preclinical models demonstrate that PTEN loss promotes metastasis and fibrosis, and facilitates the conversion of immune cells into immunosuppressive regulatory T cells (Treg). However, targeting PTEN loss-mediated immunosuppression can reverse immunotherapy resistance in NSCLC.