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|Ref Type||Journal Article|
|Authors||Peng W, Chen JQ, Liu C, Malu S, Creasy C, Tetzlaff MT, Xu C, McKenzie JA, Zhang C, Liang X, Williams LJ, Deng W, Chen G, Mbofung R, Lazar AJ, Torres-Cabala CA, Cooper ZA, Chen PL, Tieu TN, Spranger S, Yu X, Bernatchez C, Forget MA, Haymaker C, Amaria R, McQuade JL, Glitza IC, Cascone T, Li HS, Kwong LN, Heffernan TP, Hu J, Bassett RL, Bosenberg MW, Woodman SE, Overwijk WW, Lizée G, Roszik J, Gajewski TF, Wargo JA, Gershenwald JE, Radvanyi L, Davies MA, Hwu P|
|Title||Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy.|
|Abstract Text||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.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.|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|PTEN loss||melanoma||sensitive||GSK2636771||Preclinical||Actionable||In a preclinical study, human melanoma cells with PTEN loss were sensitive to GSK2636771, resulting in decreased activation of Akt and some inhibition of tumor growth (PMID: 26645196).||26645196|
|BRAF mut PTEN loss||melanoma||sensitive||GSK2636771 + Pembrolizumab||Preclinical||Actionable||In a preclinical study, a melanoma mouse model harboring a BRAF mutation and PTEN loss was sensitive to the combination of GSK2636771 and Keytruda (pembrolizumab), demonstrating greater tumor growth inhibition and improved survival when compared to either therapy alone (PMID: 26645196).||26645196|
|BRAF mut PTEN loss||melanoma||no benefit||GSK2636771||Preclinical||Actionable||In a preclinical study, GSK2636771 resulted in no benefit in a melanoma mouse model co-harboring a BRAF mutation and PTEN loss (PMID: 26645196).||26645196|
|PTEN dec exp||melanoma||decreased response||Nivolumab||Clinical Study - Cohort||Actionable||In a clinical study, melanoma patients with PTEN expression in less than 10% of tumor cells demonstrated decreased response to anti-PD-1 antibodies, including Opdivo (nivolumab), as compared to patients in which PTEN is present in over 10% of tumor cells (PMID: 26645196).||26645196|
|BRAF mut PTEN loss||melanoma||no benefit||Pembrolizumab||Preclinical||Actionable||In a preclinical study, Keytruda (pembrolizumab) resulted in no benefit in a melanoma mouse model co-harboring a BRAF mutation and PTEN loss (PMID: 26645196).||26645196|
|PTEN positive||melanoma||sensitive||Pembrolizumab||Clinical Study - Cohort||Actionable||In a clinical study, melanoma patients with PTEN positive tumors demonstrated a decrease in tumor size when treated with Keytruda (pembrolizumab) (PMID: 26645196).||26645196|
|BRAF V600E PTEN loss||melanoma||sensitive||GSK2636771 + unspecified PD-1 antibody||Preclinical||Actionable||In a preclinical study, treatment with the combination of GSK2636771 and a PD-1 antibody resulted in greater tumor infiltration of T-cells and tumor growth inhibition in mouse melanoma models expressing BRAF V600E with PTEN loss compared to either agent alone (PMID: 26645196).||26645196|
|PTEN positive||melanoma||sensitive||Nivolumab||Clinical Study - Cohort||Actionable||In a clinical study, melanoma patients with PTEN positive tumors demonstrated a decrease in tumor size when treated with Opdivo (nivolumab) (PMID: 26645196).||26645196|
|PTEN dec exp||melanoma||decreased response||Pembrolizumab||Clinical Study - Cohort||Actionable||In a clinical study, melanoma patients with PTEN expression in less than 10% of tumor cells demonstrated decreased response to anti-PD-1 antibodies, including Keytruda (pembrolizumab), compared to patients in which PTEN is present in over 10% of tumor cells (PMID: 26645196).||26645196|