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Cancer Discov. 2016 Feb;6(2):202-16. doi: 10.1158/2159-8290.CD-15-0283. Epub 2015 Dec 8.

Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy.

Author information

1
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
3
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
4
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
5
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
6
Department of Pathology, University of Chicago, Chicago, Illinois.
7
Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
8
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
9
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
10
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
11
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
12
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
13
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
14
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. phwu@mdanderson.org mdavies@mdanderson.org.

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.

PMID:
26645196
PMCID:
PMC4744499
DOI:
10.1158/2159-8290.CD-15-0283
[Indexed for MEDLINE]
Free PMC Article

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