PTEN‐deficient prostate cancer is associated with an immunosuppressive tumor microenvironment mediated by increased expression of IDO1 and infiltrating FoxP3+ T regulatory cells

Abstract

Background: Accumulating evidence shows that tumor cell-specific genomic changes can influence the cross talk between cancer cells and the surrounding tumor microenvironment (TME). Loss of the PTEN tumor suppressor gene is observed in 20% to 30% of prostate cancers (PCa) when first detected and the rate increases with PCa progression and advanced disease. Recent findings implicate a role for PTEN in cellular type I interferon response and immunosuppression in PCa. However, the way that PTEN inactivation alters antitumor immune response in PCa is poorly understood. Materials and Methods:To investigate the changes associated with PTEN loss and an immunosuppressive TME in PCa, we used CIBERSORT to estimate the relative abundance of 22 immune-cell types from 741 primary and 96 metastatic tumors. Our in silico findings were then validated by immunohistochemical analysis of immune cells and IDO1 and PDL1 checkpoint proteins in a cohort of 94 radical prostatectomy specimens.Results: FoxP3+ T regulatory cells (Tregs) were significantly increased in PTENdeficient PCa in all three public domain cohorts. Loss of PTEN in bone metastases was associated with lower CD8+ T-cell abundance, but in liver metastasis, FoxP3+ Tregs were present at higher levels. PTEN-deficient lymph node metastasis had a distinct profile, with high levels of CD8+ T cells. Moreover, we found that metastatic PCa presents higher abundance of FoxP3+ Treg when compared to primary lesions. Since PTEN-deficient tumors are likely to be immunosuppressed as a consequence of increased FoxP3+ Tregs, we then evaluated the localization and expression of IDO1, PDL1 immune checkpoints, and the corresponding density of FoxP3+ Treg and CD8+ T cells using our validation cohort (n = 94). We found that IDO1 protein expression and FoxP3+ Treg density were higher in neoplastic glands compared with benign adjacent tissue. Moreover, higher densities of FoxP3+ Treg cells in both stromal The Prostate. 2019;79:969-979.wileyonlinelibrary.com/journal/pros

Is there a causal link between PTEN deficient tumors and immunosuppressive tumor microenvironment?

“…The mouse PDAC driven by oncogenic Kras and PTEN loss promotes marked nuclear factor kappa B (NF-κB) activation and its cytokine network, with accompanying robust stromal activation and immune cell infiltration [43]. Recently, PTEN deficiency has been linked to an immunosuppressive state in prostate cancer with distinct changes in the frequency of immune cell types in tumors from different metastatic sites [29]. Forkhead box P3 + (FoxP3 + ) regulatory T cells (Treg) cells and overexpression of indoleamine 2,3-dioxygenase 1 (IDO1) protein were reported as the source of immunosuppression [29] (Fig.…”

“…Recently, PTEN deficiency has been linked to an immunosuppressive state in prostate cancer with distinct changes in the frequency of immune cell types in tumors from different metastatic sites [29]. Forkhead box P3 + (FoxP3 + ) regulatory T cells (Treg) cells and overexpression of indoleamine 2,3-dioxygenase 1 (IDO1) protein were reported as the source of immunosuppression [29] (Fig. 2).…”

“…IFNs can be activated through intra-and extra tumor mechanisms to induce immune cells to effectively eliminate tumors and overcome the immunosuppressive tumor microenvironment. [27] and Tregs [29]. JAK/STAT pathway is activated [23], IDO1 protein [29], PD-1 receptors [22] and inhibitory cytokines [23,25,27] are upregulated.…”

“…[27] and Tregs [29]. JAK/STAT pathway is activated [23], IDO1 protein [29], PD-1 receptors [22] and inhibitory cytokines [23,25,27] are upregulated. CD4 + , CD8 + and NK cells exhibited reduced infiltration [23,25].…”

“…PTEN's role in tumor suppression * PTEN deficiency is observed in nearly 40% of glioblastoma [14] * PTEN contributes to repair of DNA damage via the homologous recombination pathway [7] * PTEN deficiency is associated with malignant transformation, chemotherapy resistance and reduced survival [8][9][10][11] Tumors with PTEN deficiency have dysregulated infiltration of immune cells * High levels of MDSCs [27] and Tregs [29] in the TME of PTEN deficient tumors * Reduced infiltration of CD4 + , CD8 + and NK cells [23,25] and reduced lysing activities of cytotoxic T lymphocytes depending on the granzyme and perforin depletion [25,26] PTEN's role in type 1 IFN pathway * Type 1 IFN pathway promotes anti-tumor immunity [49] * PTEN is required for activation of STING mediated induction of interferon alpha/beta gene expression [67] Potential ways in which PTEN deficient tumors can be targeted by immunotherapies * Activation of interferon alpha/beta signaling [89,91] * Engineered PTENα expressing oncolytic viruses can enhance the development of antitumor immunity [96] Page 9 of 11 Cetintas and Batada J Transl Med (2020) 18:45 Abbreviations AC: adenocarcinoma; AKT: AKT serine/threonine kinase; APCs: antigen presenting cells; BCR: B cell receptor; cAMP: cyclic-AMP; CCL2: C-C motif chemokine ligand-2; CTLs: cytotoxic T lymphocytes; CTLA-4: cytotoxic T-lymphocyte associated protein 4; DCs: dendritic cells; DLBCL: diffuse large B-cell lymphoma; FGFR2: fibroblast growth factor receptor 2; FoxP3: Forkhead box P3; GBM: glioblastoma; HR: homologous recombination; ICIs: immune checkpoint inhibitors; IDO1: indoleamine 2,3-dioxygenase 1; IFN: interferon; IL: interleukin; IRF3: interferon regulatory factor 3; ISGs: interferon stimulated genes; MDSCs: myeloid-derived suppressor cells; NF-κB: nuclear factor kappa-B; NK: natural killer; PDAC: pancreatic ductal adenocarcinoma; PIK3CA: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PI3K: phosphoinositide-3-kinase; PIK3: phosphatidyl inositol 3-kinase; PTEN: phosphatase and tensin homolog; PIP3: phosphatidylinositol 3,4,5-trisphosphate; RT: radiotherapy; SASP: senescence associated secretory phenotype; SCC: squamous cell carcinoma; SHP2: Src homology-2 domain-containing phosphatase-2; STING: stimulator of interferon gene; NSCLC: non-small cell lung cancer; TAMs: tumorassociated macrophages; TME: tumor microenvironment; TMZ: temozolomide; TNBCs: triple-negative breast cancers; TNFα: tumor necrosis factor-α; Tregs: regulatory T cells; VEGF: vascular endothelial growth factor-A.…”