PTEN Loss Confers Resistance to Anti-PD-1 Therapy in Non-Small Cell Lung Cancer by Increasing Tumor Infiltration of Regulatory T Cells
Francisco Exposito 1 2 3 4 , Miriam Redrado 1 3 , Maeva Houry 1 , Katherine Hastings 5 6 7 , Magdalena Molero-Abraham 8 , Teresa Lozano 9 , Jose Luis Solorzano 10 , Julian Sanz-Ortega 11 , Vera Adradas 8 , Ramon Amat 12 , Esther Redin 1 2 3 4 , Sergio Leon 1 4 , Naroa Legarra 1 , Javier Garcia 4 , Diego Serrano 1 3 4 , Karmele Valencia 1 2 , Camila Robles-Oteiza 13 , Giorgia Foggetti 5 6 7 , Nerea Otegui 1 4 , Enriqueta Felip 12 , Juan J Lasarte 3 9 , Luis Paz-Ares 2 8 , Jon Zugazagoitia 2 8 , Katerina Politi 5 6 7 , Luis Montuenga # 1 2 3 4 , Alfonso Calvo # 1 2 3 4
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 TGFβ/CXCL10 to promote conversion of CD4+ 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-TGFβ 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 immunotherapy resistance in LUSCs by establishing an immunosuppressive tumor microenvironment that can be reversed therapeutically.
CITA DEL ARTÍCULO Cancer Res. 2023 Aug 1;83(15):2513-2526. doi: 10.1158/0008-5472.CAN-22-3023