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Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy
Weiyi Peng1, Jie Qing Chen1, Chengwen Liu1
1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Unlabelled:
T cell-mediated immunotherapies are promising cancer treatments. However, most patients still fail to respond to these therapies. The molecular determinants of immune resistance are poorly understood. We show that loss of PTEN in tumor cells in preclinical models of melanoma inhibits T cell-mediated tumor killing and decreases T-cell trafficking into tumors. In patients, PTEN loss correlates with decreased T-cell infiltration at tumor sites, reduced likelihood of successful T-cell expansion from resected tumors, and inferior outcomes with PD-1 inhibitor therapy. PTEN loss in tumor cells increased the expression of immunosuppressive cytokines, resulting in decreased T-cell infiltration in tumors, and inhibited autophagy, which decreased T cell-mediated cell death. Treatment with a selective PI3Kβ inhibitor improved the efficacy of both anti-PD-1 and anti-CTLA-4 antibodies in murine models. Together, these findings demonstrate that PTEN loss promotes immune resistance and support the rationale to explore combinations of immunotherapies and PI3K-AKT pathway inhibitors.
Significance:
This study adds to the growing evidence that oncogenic pathways in tumors can promote resistance to the antitumor immune response. As PTEN loss and PI3K-AKT pathway activation occur in multiple tumor types, the results support the rationale to further evaluate combinatorial strategies targeting the PI3K-AKT pathway to increase the efficacy of immunotherapy.
Insights
Loss of PTEN in cancer cells hinders T cell attacks and immunotherapy effectiveness. Targeting the PI3K-AKT pathway may overcome this immune resistance, improving cancer treatment outcomes.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- T cell-mediated immunotherapies offer promise for cancer treatment but face significant patient non-response rates.
- The molecular mechanisms underlying resistance to cancer immunotherapy remain incompletely understood.
- PTEN (Phosphatase and tensin homolog) is a tumor suppressor frequently lost in various cancers.
Purpose of the Study:
- To investigate the role of PTEN loss in tumor cells on T cell-mediated anti-tumor immunity.
- To determine the impact of PTEN loss on patient response to immunotherapy.
- To explore therapeutic strategies to overcome PTEN-driven immune resistance.
Main Methods:
- Utilized preclinical models of melanoma to assess T cell activity and trafficking.
- Analyzed PTEN status, T cell infiltration, and T cell expansion in patient tumor samples.
- Investigated the effects of PTEN loss on immunosuppressive cytokine expression and autophagy.
- Evaluated the efficacy of PI3Kβ inhibitors in combination with immune checkpoint inhibitors in murine models.
Main Results:
- PTEN loss in tumor cells significantly inhibited T cell-mediated tumor killing and reduced T cell infiltration in preclinical models.
- In patients, PTEN loss correlated with decreased T cell infiltration, impaired T cell expansion, and poorer outcomes with PD-1 inhibitor therapy.
- PTEN loss upregulated immunosuppressive cytokines and inhibited autophagy, further hindering anti-tumor T cell responses.
- Combination therapy with a PI3Kβ inhibitor and immune checkpoint antibodies (anti-PD-1, anti-CTLA-4) enhanced anti-tumor efficacy in murine models.
Conclusions:
- PTEN loss in cancer cells is a key mechanism promoting resistance to T cell-mediated anti-tumor immunity.
- Targeting the PI3K-AKT pathway, in combination with immunotherapy, presents a promising strategy to enhance treatment efficacy in PTEN-deficient tumors.
- These findings support the clinical evaluation of combined immunotherapy and PI3K-AKT pathway inhibition for broader patient benefit.
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