Abstract
BackgroundRecent evidences had shown that loss in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was associated with immunotherapy resistance, which may be attributed to the non-T-cell-inflamed tumor microenvironment. The impact of PTEN loss on tumor microenvironment, especially regarding T cell infiltration across tumor types is not well understood.MethodsUtilizing The Cancer Genome Atlas (TCGA) and publicly available dataset of immunotherapy, we explored the correlation of PTEN expressing level or genomic loss with tumor immune microenvironment and response to immunotherapy. We further investigated the involvement of PI3K-AKT-mTOR pathway activation, which is known to be the subsequent effect of PTEN loss, in the immune microenvironment modulation.ResultsWe reveal that PTEN mRNA expression is significantly positively correlated with CD4/CD8A gene expression and T cells infiltration especially T helpers cells, central memory T cell and effector memory T cells in multiples tumor types. Genomic loss of PTEN is associated with reduced CD8+ T cells, type 1 T helper cells, and increased type 2 T helper cells, immunosuppressed genes (e.g. VEGFA) expression. Furthermore, T cell exclusive phenotype is also observed in tumor with PI3K pathway activation or genomic gain in PIK3CA or PIK3CB. PTEN loss and PI3K pathway activation correlate with immunosuppressive microenvironment, especially in terms of T cell exclusion. PTEN loss predict poor therapeutic response and worse survival outcome in patients receiving immunotherapy.ConclusionThese data brings insight into the role of PTEN loss in T cell exclusion and immunotherapy resistance, and inspires further research on immune modulating strategy to augment immunotherapy.
Highlights
Recent evidences had shown that loss in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was associated with immunotherapy resistance, which may be attributed to the non-T-cell-inflamed tumor microenvironment
To investigate the influence of PTEN loss on immune microenvironment across solid tumors, and to decide the involvement of phosphatidylinositol 3-kinase (PI3K)-AKT-mTOR pathway amidst, we performed an integrative analysis of The Cancer Genome Atlas (TCGA) to clarify the correlation of immune cells infiltration with PTEN loss as well as PI3KAKT-mTOR pathway activation. We found that both PTEN loss and activation of PI3K pathway were associated with reduced T cell infiltration and enhanced immune suppressive status in multiple tumor types
PTEN expression is positively correlated with T cell infiltration To investigate the impact of PTEN expression on T cell infiltration, the correlation between mRNA expression of PTEN and T cell specific genes (CD4, CD8A) in different solid tumor were determined by Pearson correlation analysis
Summary
Recent evidences had shown that loss in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was associated with immunotherapy resistance, which may be attributed to the non-T-cell-inflamed tumor microenvironment. The impact of PTEN loss on tumor microenvironment, especially regarding T cell infiltration across tumor types is not well understood. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is well known as the tumor suppressor gene for its negative regulation on phosphatidylinositol 3-kinase (PI3K) pathway [1]. Intrinsic resistance is widely exist among patients, though the mechanism of which is not clearly understood. Previous studies tried to approach this issue from the perspective of tumor microenvironment (TME) and found that non-T-cell-inflamed tumor microenvironment was closely associate with poor therapeutic response to immunotherapy, with anti-PD-1 antibodies [14, 15]. Great effort is still ongoing to decipher the underlying genomic or molecular mechanism for immune exclusion [16,17,18]
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