PTEN Loss Confers Resistance to Anti-PD-1 Therapy in Non-Small Cell Lung Cancer by Increasing Tumor Infiltration of
Francisco Exposito1,2,3,4, Miriam Redrado1,3, Maeva Houry1
1Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
Abstract:
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.
Significance:
PTEN loss leads to the development of an immunosuppressive microenvironment in lung cancer that confers resistance to anti-PD-1 therapy, which can be overcome by targeting PTEN loss-mediated immunosuppression.
Insights
Loss of PTEN in non-small cell lung cancer (NSCLC) creates an immunosuppressive tumor microenvironment, causing resistance to anti-programmed cell death protein 1 (anti-PD-1) immunotherapy. This resistance can be overcome by targeting PTEN loss-mediated immunosuppression.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Immunotherapy resistance in non-small cell lung cancer (NSCLC) is a significant clinical challenge.
- The tumor microenvironment plays a crucial role in modulating immune responses to cancer.
- Genetic alterations, particularly in the PTEN/PI3K/AKT/mTOR pathway, are common in NSCLC.
Purpose of the Study:
- To investigate the role of PTEN loss in mediating immunotherapy resistance in NSCLC.
- To elucidate the mechanisms by which PTEN loss contributes to an immunosuppressive tumor microenvironment.
- To explore therapeutic strategies to overcome PTEN loss-driven immunotherapy resistance.
Main Methods:
- Analysis of genetic alterations and PTEN expression in NSCLC patient tumors.
- Development and utilization of a Pten-null LUSC mouse model.
- Assessment of immune cell infiltration, cytokine profiles, and response to anti-PD-1 therapy.
- Evaluation of combination therapy involving TLR agonists and anti-TGFβ antibody.
Main Results:
- PTEN loss or low expression was observed in over 25% of NSCLC patients, particularly in lung squamous cell carcinomas (LUSC).
- PTEN-low tumors exhibited higher PD-L1/PD-L2 expression, resistance to anti-PD-1 therapy, increased metastasis, and fibrosis.
- PTEN loss promoted the conversion of CD4+ lymphocytes to regulatory T cells (Tregs) via TGFβ/CXCL10 secretion, leading to an immunosuppressive microenvironment enriched in Tregs.
- Combination therapy with TLR agonists and anti-TGFβ antibody resulted in complete tumor rejection and immunologic memory in mice with Pten-null tumors.
Conclusions:
- PTEN loss is a key driver of immunotherapy resistance in LUSC by establishing an immunosuppressive tumor microenvironment.
- Targeting PTEN loss-mediated immunosuppression, through strategies like combination therapy with TLR agonists and anti-TGFβ, can effectively overcome resistance to anti-PD-1 therapy.
- These findings highlight the therapeutic potential of targeting the PTEN/PI3K/AKT/mTOR pathway and its downstream effects to enhance immunotherapy efficacy in NSCLC.
