PTEN loss confers resistance to anti-PD-1 therapy in non-small cell lung cancer by increasing tumor infiltration of regulatory T cells.
Francisco ExpósitoMiriam RedradoMaeva HouryKatherine HastingsMagdalena MoleroTeresa LozanoJosé Luis SolórzanoJulián SanzVera AdradasRamon AmatEsther RedinSergio LeonNaroa LegarraJavier GarciaAngel RodriguezKarmele ValenciaCamila Robles-OteízaGiorgia FoggettiNerea OteguiEnriqueta Felip FontJuan Jose LasarteLuis G Paz-AresJon ZugazagoitiaKaterina PolitiLuis M MontuengaAlfonso CalvoPublished in: Cancer research (2023)
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 Pten-null LUSC mouse model revealed that tumors with PTEN loss were refractory to anti-PD-1, highly metastatic and fibrotic, and secreted TGF-β/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-β 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.
Keyphrases
- regulatory t cells
- pi k akt
- cell proliferation
- small cell lung cancer
- signaling pathway
- dendritic cells
- mouse model
- free survival
- stem cells
- squamous cell carcinoma
- toll like receptor
- genome wide
- inflammatory response
- dna methylation
- poor prognosis
- working memory
- single cell
- cell therapy
- high grade
- binding protein
- bone marrow
- idiopathic pulmonary fibrosis
- transcription factor
- systemic sclerosis
- type diabetes
- low grade
- newly diagnosed