title: Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Weiyi
authors.initials: W
authors.lastname: Peng
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jie Qing
authors.initials: JQ
authors.lastname: Chen
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chengwen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Shruti
authors.initials: S
authors.lastname: Malu
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Creasy
authors.affiliation: 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.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Tetzlaff
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chunyu
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jodi A
authors.initials: JA
authors.lastname: McKenzie
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chunlei
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Xiaoxuan
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Leila J
authors.initials: LJ
authors.lastname: Williams
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Wanleng
authors.initials: W
authors.lastname: Deng
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Guo
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Rina
authors.initials: R
authors.lastname: Mbofung
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lazar
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Torres-Cabala
authors.affiliation: 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.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Cooper
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Pei-Ling
authors.initials: PL
authors.lastname: Chen
authors.affiliation: Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Trang N
authors.initials: TN
authors.lastname: Tieu
authors.affiliation: Department of Pathology, University of Chicago, Chicago, Illinois.
authors.forename: Stefani
authors.initials: S
authors.lastname: Spranger
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chantale
authors.initials: C
authors.lastname: Bernatchez
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Marie-Andree
authors.initials: MA
authors.lastname: Forget
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Cara
authors.initials: C
authors.lastname: Haymaker
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Rodabe
authors.initials: R
authors.lastname: Amaria
authors.affiliation: Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: McQuade
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Isabella C
authors.initials: IC
authors.lastname: Glitza
authors.affiliation: Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Tina
authors.initials: T
authors.lastname: Cascone
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Haiyan S
authors.initials: HS
authors.lastname: Li
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Lawrence N
authors.initials: LN
authors.lastname: Kwong
authors.affiliation: Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Heffernan
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Roland L
authors.initials: RL
authors.lastname: Bassett
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Marcus W
authors.initials: MW
authors.lastname: Bosenberg
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Woodman
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Willem W
authors.initials: WW
authors.lastname: Overwijk
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gregory
authors.initials: G
authors.lastname: Lizée
authors.affiliation: 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.
authors.forename: Jason
authors.initials: J
authors.lastname: Roszik
authors.affiliation: Department of Pathology, University of Chicago, Chicago, Illinois.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Gajewski
authors.affiliation: 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.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Gershenwald
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Radvanyi
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. phwu@mdanderson.org mdavies@mdanderson.org.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. phwu@mdanderson.org mdavies@mdanderson.org.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage* / Q000627:therapeutic use; D060908:CTLA-4 Antigen / Q000276:immunology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology; D051379:Mice; D009025:Morpholines / Q000008:administration & dosage / Q000627:therapeutic use; D051059:PTEN Phosphohydrolase / Q000172:deficiency*; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000631:Aminopyridines; D000906:Antibodies; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D009025:Morpholines; C571178:NVP-BKM120; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human