Loss of PTEN Promotes Resistance to T Cell–Mediated Immunotherapy
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Abstract
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. Cancer Discov; 6(2); 202–16. ©2015 AACR. See related commentary by Rizvi and Chan, p. 128. This article is highlighted in the In This Issue feature, p. 109
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Tumor-intrinsic activation of the Wnt/β-catenin pathway and deletion or mutation of Pten lead to deficient T cell infiltration into the tumor microenvironment and resistance to checkpoint blockade immunotherapy.
“Tumor-intrinsic activation of the Wnt/β-catenin pathway (15) and deletion or mutation of Pten (16) have been shown to lead to deficient T cell infiltration into the tumor microenvironment and resistance to checkpoint blockade immunotherapy.”
From The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients (2018) · cites this paper as [16]
Inhibition of the PI3K/AKT/mTOR pathway improves the efficacy of anti-PD-1 and anti-CTLA-4 antibodies in mouse models.
“Inhibition of the PI3K/AKT/mTOR pathway improves the efficacy of anti-PD-1 and anti-CTLA-4 antibodies in mouse models [226,230,231].”
From Drug Resistance in Colorectal Cancer: From Mechanism to Clinic (2022) · cites this paper as [230]
Combinatorial biomarker strategies that capture host and tumor-immune ecosystem features are essential.
“Combinatorial biomarker strategies that capture attributes of the host and tumor-immune ecosystem will be essential (Fig. 2; refs.121-124).”
From The Next Decade of Immune Checkpoint Therapy (2021) · cites this paper as [124]
PTEN loss is associated with increased PI3K-AKT signaling and correlates with CD8 T-cell exclusion and poor clinical responses to immune checkpoint therapy.
“In addition, PTEN loss is also associated with increased signaling through the PI3K-AKT pathway and correlated with exclusion of CD8 T cells and poor clinical responses to ICT (124).”
From The Next Decade of Immune Checkpoint Therapy (2021) · cites this paper as [124]
PTEN competence is associated with a higher incidence of PD-L1+ cases in melanoma patients.
“PTEN competence is associated with an increased incidence of PD-L1 cases in melanoma patients (Peng et al., 2016)”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Peng et al., 2016
PTEN silencing in melanoma cells does not affect PD-L1 levels.
“PTEN silencing in melanoma cells fails to affect PD-L1 levels (Peng et al., 2016)”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Peng et al., 2016
PTEN loss decreased the number and cytolytic activity of CD8+ T cells in tumors and promoted resistance to T cell-induced tumor apoptosis.
“PTEN loss decreased the number and the cytolytic activity of CD8+ T cells in tumors and also promoted resistance to T cell-induced tumor apoptosis (Peng et al., 2016).”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Peng et al., 2016
PTEN loss correlated with poor response to PD-1 antibodies in melanoma and could be reversed by PI3Kβ inhibition.
“PI3K activation as a result of phosphatase and tensin homolog (PTEN) loss was correlated with a poor response to PD-1 antibodies in melanoma and could be reversed by PI3Kβ inhibition.”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Peng et al., 2016
PTEN expression represses PD-L1 expression, promoting an immune response against tumor cells.
“PTEN expression represses PD-L1 expression, promoting an immune response against tumor cells.”
From Mechanisms and prevention of <scp>UV</scp>‐induced melanoma (2018) · cites this paper as [115]
Loss of PTEN in melanoma cells allows PI3K-mediated activation of immunosuppressive cytokines.
“Loss of PTEN in melanoma cells allows PI3K-mediated activation of immunosuppressive cytokines114,115.”
From Mechanisms and prevention of <scp>UV</scp>‐induced melanoma (2018) · cites this paper as [115]
PTEN loss is associated with non-brisk, localized immune response in tumors.
“PTEN loss was associated with non-brisk (localized) immune response in tumors114,115.”
From Mechanisms and prevention of <scp>UV</scp>‐induced melanoma (2018) · cites this paper as [115]
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- Authors
- Peng, W., Chen, J. Q., Liu, C., Malu, S., Creasy, C., Tetzlaff, M. T., Xu, C., McKenzie, J. A., Zhang, C., Liang, X., Williams, L. J., Deng, W., Chen, G., Mbofung, R., Lazar, A. J., Torres-Cabala, C. A., Cooper, Z. A., Chen, P.-L., Tieu, T. N., Spranger, S., Yu, X., Bernatchez, C., Forget, M.-A., Haymaker, C., Amaria, R., McQuade, J. L., Glitza, I. C., Cascone, T., Li, H. S., Kwong, L. N., Heffernan, T. P., Hu, J., Bassett, R. L., Bosenberg, M. W., Woodman, S. E., Overwijk, W. W., Lizée, G., Roszik, J., Gajewski, T. F., Wargo, J. A., Gershenwald, J. E., Radvanyi, L., Davies, M. A., & Hwu, P.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- University of Chicago (US)
- 1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- Yale University (US)
- Corresponding author
- Hwu, Patrick
- ORCID
- Peng, Weiyi
- Liu, Chengwen
- Creasy, Caitlin
- Tetzlaff, Michael T.
- Xu, Chunyu
- McKenzie, Jodi A.
- Zhang, Chunlei
- Williams, Leila J.
- Mbofung, Rina
- Lazar, Alexander J.
- Torres-Cabala, Carlos A.
- Cooper, Zachary A.
- Chen, Pei-Ling
- Spranger, Stefani
- Yu, Xiaoxing
- Bernatchez, Chantale
- Haymaker, Cara
- Amaria, Rodabe
- McQuade, Jennifer L.
- Cascone, Tina
- Li, Haiyan S.
- Kwong, Lawrence N.
- Heffernan, Timothy P.
- Hu, Jianhua
- Bassett, Roland L.
- Bosenberg, Marcus W.
- Woodman, Scott E.
- Roszik, Jason
- Gajewski, Thomas F.
- Wargo, Jennifer A.
- Gershenwald, Jeffrey E.
- Radvanyi, Laszlo
- Davies, Michael A.
- Hwu, Patrick
- Venue
- Cancer Discovery
- Published
- 2016-02-01
- Volume
- 6
- Issue
- 2
- Pages
- 202-216
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC4744499
- OpenAlex
- W2201379305
- Cited by
- 1,539
- References
- 54
- Citations by year
- 2026: 88 · 2025: 134 · 2024: 131 · 2023: 157 · 2022: 176 · 2021: 204 · 2020: 209 · 2019: 150 · 2018: 124 · 2017: 110 · 2016: 53 · 2015: 1
- FWCI
- 41.93
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000371)
- National Cancer Institute (K99CA204595, U54CA163125, T32CA009666, R00CA204595, P01CA128913, R01CA154710, K08CA160692, R01CA116206, P30CA016672, P30CA016359, P50CA093459, R01CA187076)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- PTEN loss, melanoma, PD-1 inhibitors, CTLA-4, T cell infiltration, PI3K/Akt signaling, autophagy, immunosuppressive cytokines, tumor immune microenvironment, combination immunotherapy
- MeSH terms
- Aminopyridines, Animals, Antibodies, Drug Synergism, Humans, Immunotherapy, Melanoma, Morpholines, T-Lymphocytes, Drug Resistance, Neoplasm, Cell Line, Tumor, PTEN Phosphohydrolase, Mice, CTLA-4 Antigen, Programmed Cell Death 1 Receptor
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