Revising PTEN in the Era of Immunotherapy: New Perspectives for an Old Story
Abstract
:1. Introduction
2. PTEN Function in Tumor-Immune Microenvironment
3. PTEN Pathway in Regulatory T Cells: A Controversial Role
4. PTEN-Modulating Strategies
4.1. Inhibition of PTEN Function
4.2. Reactivation of PTEN Pathway
5. PTEN Role in Immunotherapy Response
5.1. Immunotherapy
5.2. PTEN and Immunotherapy Resistance
5.3. AKT Pathway and Adoptive Cell Transfer Therapy
6. Ongoing Clinical Trials
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Tumor Type | Tumor Model | Consequence for Immune Regulation and Tumor Immune Microenvironment | Mechanism Involved | Reference |
---|---|---|---|---|
Melanoma | Patient-derived short-term melanoma cultures that either naturally express or lacked PTEN gene; PTEN knock-down/knock-in melanoma cell lines. | Increase of IL-10, IL-6 and VEGF; reduction of secretion of the pro-inflammatory cytokine IL-12 by monocyte-derived dendritic cells. | In melanoma cells lacking PTEN, STAT3 activated the transcription of immunosuppressive cytokines in a PI3K-dependent manner. Moreover, PD-L1 was upregulated, leading to immune evasion. | Dong et al., Oncogene 2014 [27] |
Melanoma | Genetically engineered mouse models with specific deletion of PTEN in Tregs (PTENTreg-KO mice). | Intra-tumor increment of activated proinflammatory Ly6c+CD11b+ myeloid dendritic cells, which expressed more CD86 and less PD-L1. Tregs in the tumor lost their suppressive phenotype and converted into proinflammatory helper cells (ex-Tregs). | Genetically modified mice with specific deletion of PTEN in Tregs showed Treg destabilization, slow melanoma tumor growth, high grade of inflammation and were not able to create an immunosuppressive tumor microenvironment. | Sharma et al., Science advances 2015 [28] |
Melanoma | Mouse model bearing PTEN deleted melanoma tumors. | Decreased of T cell trafficking in tumor bulk in adoptive T cell therapy mouse models. | Loss of PTEN promoted resistance to T cell killing and decresed T cell infiltration by inducing expression of immunomodulatory cytokines, such as CCL2 or VEGF, and inhibiting autophagy pathway. | Peng et al., Cancer discovery 2016 [29] |
Prostate tumor | Mice bearing PTEN-null senescent prostate tumors. | Increase of tumor infiltration of MDSCs. Reduction of CD4+, CD8+ and natural killer (NK) infiltrates. | In PTEN-null senescent tumors, activation of the JAK2/STAT3 pathway via protein tyrosine phosphatase PTPN11/SHP2 established an immunosuppressive tumor microenvironment with production of MDSC chemoattractant cytokines. | Toso et al., Cell reports 2014 [30] |
Prostate tumor | Genetically engineered mouse models with specific deletion of PTEN in prostate epithelial cells (Ptenpc−/− mice). | Increase of tumor infiltration of MDSCs. | The massive infiltration of MDSCs induced secretion of IL-1 receptor antagonist (IL-1RA) that hampers senescence response thus sustaining tumor growth. | Di Mitri et al., Nature 2014 [31] |
Prostate tumor | Genetically engineered mouse models with specific prostate deletion of PTEN (Ptenpc−/− mice), PTEN and Zbtb7a (Ptenpc−/−; Zbtb7apc−/− mice), PTEN and p53 (Ptenpc−/−; Trp53pc−/− mice) and organoid cultures. | Increase of tumor infiltration of MDSCs. | Combined deletion of PTEN and Zbtb7a or PTEN and p53 in prostate tumors promoted tumor progression through MDSC recruitment, NF-κB signalling activation and cytokines secretion. | Bezzi et al., Nature medicine 2018 [32] |
Pancreatic ductal adenocarcinoma (PDAC) | Genetically engineered mouse models with specific pancreatic deletion of PTEN (Pdx1-Cre, KrasG12D and PtenL mice). | Increase of tumor infiltration of MDSCs, neutrophils, monocytes and Tregs. | PTEN loss induced secretion of chemoattractant cytokines CXCL1, G-CSF, IL-23 via NFkB. | Ying et al., Cancer discovery 2011 [33] |
Brain metastatic tumor | Co-culture of tumour cells with primary glia (90% astrocytes). Mouse model obtained by intracarotidly injection of syngeneic mouse melanoma B16BL6 cells to form brain metastase with or whitout astrocyte-specific depletion of PTEN-targeting miRNAs. | Recruitment of ionized calcium-binding adapter molecule 1 (IBA1)-expressing myeloid cells. | Astrocyte-derived exosomes mediated an intercellular transfer of PTEN-miRNAs to brain metastatic tumor cells to simulate transient PTEN loss status which in turn induced secretion of CCL2 with recruitment of IBA1-expressing myeloid cells, thus further enhancing metastasis outgrowth. | Zhang et al., Nature 2015 [34] |
Breast cancer | Genetically engineered mouse models with specific inactivation of Pten in stromal fibroblasts of mouse mammary glands. | Massive remodeling of the extra-cellular matrix (ECM), enhanced deposition of collagen, innate immune cell infiltration and increased angiogenesis. | Loss of PTEN in stromal fibroblasts Sustained tumor growth through an Ets2-dependent transcriptional program with induction of MMP9 and CCL3 and VEGF pathway. | Trimboli et al., Nature 2009 [35] |
Breast cancer | Genetically engineered mouse models with specific delection of PTEN in fibroblast. | Increase of MMP9, MMP2, BMP1, LOXL2 and EMILIN2, increased angiogenesis. | PTEN loss from mammary stromal fibroblasts activates an oncogenic secretome that orchestrates the transcriptional reprogramming of other cell types in the microenvironment. Downregulation of miR-320 and upregulation of one of its direct targets ETS2, are critical events in Pten-deleted stromal fibroblasts responsible for inducing this oncogenic secretome, which in turn promotes tumour angiogenesis and tumour-cell invasion. | Bronisz et al., Nature cell biology 2011 [36] |
Thyroid cancer | Co-culture of PTEN-deficient thyroid cancer cell line with monocytes derived from PTEN hamartoma tumor syndrome (PHTS) patients. | Innate immune cells from PHTS patients acquired a more proinflammatory phenotype and increased lactate production. | Secretion of proinflammatory factors. | Sloot et al., Oncogene 2019 [37] |
Glioma | Glioma cell line with genetic deletions in or mutations of PTEN | Increase of immunosuppressive mileu. | Specific loss of PTEN in glioma cells induced reduction of anti-tumor immunity and resistance to tumor-specific T cells lysis with increase of PD-L1 expression through a translational regulation mechanism. | Parsa et al.,Nature medicine 2007 [38] |
Glioblastoma | Primary human glioblastoma cell lines derived from resected patients and co-cultured with matched autologous T-cells. | High T-cell apoptosis upon contact with PTEN-deficient cancer cells. | PTEN loss confered immunoresistant phenotype through the PI3K/Akt/mTOR pathway. | Waldron et al., Journal of clinical neuroscience 2010 [39] |
Gastric cancer | Mouse models treated with gastric cancer cell derived exosomes. | Increase of MDSCs activation. | Gastric cancer-secreted exosomes were able to deliver miRNA-107 to the host MDSCs inducing their activation through PTEN-downregulation. Indeed, the release of PI3K pathway induced the expression of ARG1 in MDSCs thus increasing their suppressive function. | Ren et al, Cancer Management and Research 2019 [40] |
Treatment | Tumor Type | Study Results | n. of Patients | Reference |
---|---|---|---|---|
anti-PD-1 pembrolizumab or nivolumab | Melanoma | Analysis of a cohort of 39 metastatic melanoma patients treated with anti-PD-1 antibodies (pembrolizumab and nivolumab) demonstrated that patients with PTEN positive tumors achieved significantly greater reduction of tumor size than patients with PTEN negative tumors (p = 0.029) | Cohort of 39 patients | Peng et al., Cancer discovery 2016 [29] |
anti CTLA-4 ipilimumab and/or anti-PD-1 pembrolizumab | Melanoma | Analysis of a cohort of longitudinal tissue samples from metastatic melanoma patients treated with sequential immune checkpoint blockade (CTLA-4 blockade followed by PD-1 blockade at time of progression) demonstrated that PTEN loss is associated with CTLA-4 blockade resistance. | Cohort of 56 patients | Roh et al., Science translational medicine 2017 [83] |
anti-PD-1 pembrolizumab | Uterine leiomyosarcoma | Analysis of primary tumor, the sole treatment-resistant metastasis, and germline tissue identified biallelic PTEN loss as potential clinical mechanism of acquired resistance to immune checkpoint therapy. | Case report | George et al., Immunity 2017 [84] |
anti PD-1 nivolumab or pembrolizumab | Glioblastoma | Mutations on PTEN were significantly enriched in nonresponders to anti-PD-1 inhibitors. Analysis of matched pre- and post-anti-PD-1 treatment samples showed that PTEN-mutated tumors had a significantly higher level of CD68+HLA-DR− macrophages, which was previously linked to poor survival in melanoma. | Cohort of 76 patients | Zhao et al., Nature medicine 2019 [85] |
anti-PD-1 nivolumab and anti-CTLA-4 ipilimumab | Non-small cell lung cancer (NSCLC) | PTEN mutations were significanly associated with resistence to immunocheckpoint inhibitor (p < 0.05). | Cohort of 113 patients | Chen et al., Cancer Sci. 2019 [86] |
anti PD-1 nivolumab and pembrolizumab | Non-small cell lung cancer (NSCLC) | A metastatic NSCLC case with PTEN mutation, 80% PD-L1 expression and high tumor mutational load showed a durable response to mTORC1 inhibitor but was refractory to treatment with anti-PD-1 antibodies. | Case report | Parikh et al., Lung Cancer 2018 [87] |
Conditions | Immunotherapy Treatment | Study Description | State | Estimated Enrolment | Study Identifier |
---|---|---|---|---|---|
Advanced or metastatic solid tumors | anti PD-L1 durvalumab | This is a Phase I dose-escalation study to evaluate the safety and tolerability of combination treatment of AKT inhibitor AZD5363 + PARP inhibitor olaparib + durvalumab. An exploratory objective is to explore molecular correlates of the relationship between mutations in AKT/PIK3CA/PTEN pathway and treatment response. | Recruiting | 40 participants | NCT03772561 |
Advanced solid tumors selected for specific molecular alterations, including PTEN mutation | anti PD-L1 durvalumab | This is a Phase Ib study to evaluate effects and best dose of the PI3Kinase inhibitior copanlisib and PARP inhibitor olaparib when given together with durvalumab in patients with molecularly-selected solid tumors including PTEN mutation. | Not yet recruiting | 102 participants | NCT03842228 |
Metastatic melanoma with PTEN Loss | anti-PD-1 pembrolizumab | This is a Phase I/II study to evaluate objective response rate and overall survival of the selective PI3K-Beta Inhibitor GSK2636771 in combination with pembrolizumab in patients with metastatic melanoma and PTEN Loss. | Recruiting | 41 participants | NCT03131908 |
Relapsed/refractory mismatch-repair proficient colorectal cancer | anti-PD-1 nivolumab | This is a Phase I/II study to evaluate objective response rate of PI3Kinase inhibitor copanlisib and nivolumab. | Recruiting | 54 participants | NCT03711058 |
Recurrent/refractory diffuse large B-cell lymphoma or primary mediastinal large B-cell lymphoma | anti-PD-1 nivolumab | This is a Phase II study to evaluate objective response rate of PI3Kinase inhibition copanlisib hydrochloride and nivolumab. | Suspended | 106 participants | NCT03484819 |
Metastatic triple-negative breast cancer or ovarian cancer | A2aR and A2bR antagonist AB928 | This is a Phase I/Ib study to evaluate safety, tolerability, pharmacokinetic, pharmacodynamic, and clinical activity of immunotherapy combinations. dual adenosine receptor antagonist AB928 in combination with pegylated liposomal doxorubicin with or without PI3kinase-gamma inhibitor IPI-549. | Recruiting | 214 participants | NCT03719326 |
Non Small Cell Lung Cancer | anti-PD-1 pembrolizumab | This is a Phase Ib/II study to evaluate safety and objective response rate of the standard pembrolizumab in combination with the investigational agent PI3K-delta inhibitor idelalisib. | Recruiting | 40 participants | NCT03257722 |
HLA-DPB1*04:01 positive adults with advanced cancers | T Cell Receptor Engineered T Cells (KITE-718) | This is a Phase I study to evaluate safety and objective response rate of KITE-718 treated with AKT inhibitor during manufacturing process. | Recruiting | 75 participants | NCT03139370 |
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Piro, G.; Carbone, C.; Carbognin, L.; Pilotto, S.; Ciccarese, C.; Iacovelli, R.; Milella, M.; Bria, E.; Tortora, G. Revising PTEN in the Era of Immunotherapy: New Perspectives for an Old Story. Cancers 2019, 11, 1525. https://doi.org/10.3390/cancers11101525
Piro G, Carbone C, Carbognin L, Pilotto S, Ciccarese C, Iacovelli R, Milella M, Bria E, Tortora G. Revising PTEN in the Era of Immunotherapy: New Perspectives for an Old Story. Cancers. 2019; 11(10):1525. https://doi.org/10.3390/cancers11101525
Chicago/Turabian StylePiro, Geny, Carmine Carbone, Luisa Carbognin, Sara Pilotto, Chiara Ciccarese, Roberto Iacovelli, Michele Milella, Emilio Bria, and Giampaolo Tortora. 2019. "Revising PTEN in the Era of Immunotherapy: New Perspectives for an Old Story" Cancers 11, no. 10: 1525. https://doi.org/10.3390/cancers11101525