Table 1 PTEN-mediated immunogenicity in different types of tumors
From: Is there a causal link between PTEN deficient tumors and immunosuppressive tumor microenvironment?
Tumor | Main evidence | Experimental setup and methods | |
|---|---|---|---|
Lung cancer [8] | A decrease in PTEN expression contributes to cellular unresponsiveness to IFN-γ | Cell lines PC14PE6/AS2 A549 | shRNA, plasmid transfection, WB, FC, luciferase reporter assay, intracellular ROS assay |
GBM [22] | Tumors had increased levels of B7-H1 protein and tumor-specific T cells lysed human glioma targets expressing PTENwt more effectively than those expressing PTENmutant | U87MG Cell line and primary cultures | FC, RT-PCR, IHC, WB, NB |
Prostate cancer [23] | Cytokines released by PTEN-null senescent prostate tumors drive an immunosuppressive TME, Jak2/Stat3 pathway is activated in PTENpc−/− senescent tumors | Mice models Ptenpc+/+, Ptenpc−/− Ptenpc−/−; Stat3pc−/− | MACS, Cytokine array, FACS, CD8+ suppression assay, pStat3, WB, IHC, IF, GZMB mRNA, H&E |
Melanoma [24] | PTEN negatively regulates the expression of immunosuppressive cytokines and PD-L1 by inhibiting the PI3K pathway | Cell lines (PTEN-defective vs. PTEN expressing pairs) | Expression of the IL-10, IL-6, VEGF, PI3K inhibitor treatment |
Melanoma samples lacking brisk host responses showed a higher tendency to lose PTEN | Brisk host response n = 33, without brisk host responses n = 34 | IHC (CD3 and PTEN) | |
Melanoma [25] | PTEN loss causes resistance to T cell mediated response | Cell line A375 PTENsilenced vs control | shRNA, T cell treatment, Casp3 cleavage assay |
Mice tumor model PTENsilenced vs control | Luciferase expressing T cells treatment, bioluminescence imaging, tumor size, survival | ||
PTEN absent tumor cells have lower CD8+ T cell infiltration | Clinical human samples | 135 resected tumors, IHC | |
TCGA | Lymphocyte activation score, cytolic activity, expressions of LCK, IFNγ, GZMB | ||
PTEN loss promotes resistance to immune infiltration of tumors through the production of inhibitory cytokines | Mice xenografts model PTENsilenced vs control | Chemokines and cytokines by Luminex assay | |
Clinical human samples | IHC confirmed increased VEGF in regions with PTEN loss | ||
Sarcoma [26] | PTEN loss is associated with induction of an immunosuppressive microenvironment and resistance to PD-1 blockade | Primary tumor, treatment-resistant metastatic tumor and germline tissue from a clinical case | IHC, RNA-seq and WES |
Tumors with biallelic PTEN loss had significantly lower levels of mRNA expression of PDCD1, CD8A, IFNG, PRF1, and GZMA compared to PTENwt tumors | TCGA | Mutation, copy number, RNA-seq data from 241 untreated primary sarcomas | |
Prostate cancer [27] | PTEN loss leads to upregulated inflammatory and cytokine–cytokine receptor signaling. | PTEN null murine models Cell lines | FACS, IHC, Q-RT-PCR, T cell suppression assay, laser capture and microarray |
Pro-inflammatory cytokines produced by PTEN null prostate are the major causes of MDSC expansion | |||
Lymphoma [11] | Low PTEN mRNA expression is associated with down-regulation of a group of genes involved in immune responses and B-cell development/differentiation and poorer survival | 478 cases (training cohort) 269 cases (validation cohort) | IHC, FISH, Gene sequencing and expression array |
GBM [28] | PTEN mutations associated with immuno suppressive expression signatures in ICIs non-responders | 66 patients treated with PD-1 inhibitors profiled across a variety of timepoints, collecting DNA, RNA, tissue imaging | WES, qmIF, lymphocyte clonality analysis, RNA seq |
Prostate cancer [29] | FoxP3+ Tregs were significantly increased in PTEN deficient PCa, PTEN deficiency is linked to an immunosuppressive state in PCa with distinct changes in the frequency of immune cell types in tumors from different metastatic sites | 741 primary and 96 metastatic tumors, 94 radical prostatectomy specimens for IH validation | in silico analysis and IH validation for IDO1 and PDL1 |