16P - PTEN deficiency leads to colorectal cancer immune evasion via atypical Keap1/Nrf2 pathway

Background

As a tumor suppressor gene, PTEN functions as a lipid phosphatase to dephosphorylate phosphatidylinositol (3,4,5)-trisphosphate (PIP3) to phosphatidylinositol (4,5)-bisphosphate (PIP2). In addition, more and more studies have reported its function as protein phosphatase. The frequency of PTEN deletions and mutations is 8-9% overall in colorectal cancer. Compared to the MSS-low TMB group, the mutation frequency is up to 25.1% in MSI-high TMB group and 45.3% in the MSS-high TMB group, respectively. Several studies have shown that PTEN loss is associated with immune evasion in some cancers, but the association between PTEN and immune surveillance in colorectal cancer is elusive.

Methods

BALB/c and C57BL/6 mice were used to study tumor growth and the effect of drugs(PD-1 antibody and ML385, a Nrf2 inhibitor) on tumor. Tumor immune microenvironment was assessed by flow cytometry analysis. Mass spectrum, gene ontology analysis, RNA-seq, western blot, co-immunoprecipitation, and immunofluorescence were performed to investigate how PTEN regulates Keap1/Nrf2 pathway mediated MHCI degradation.

Results

PTEN deficiency dramatically enhanced tumor growth and resulted in resistance to anti-PD-1 inhibitors and worse survival outcomes. T cell activation was weaker in the PTEN-deficient group, as shown by decreased numbers of IFNγ+, Ki67+ and Gzmb+ CD4 and CD8 T cells. PTEN overexpression improved Keap1, a new downstream molecular, protein level via its protein phosphatase function, thus suppressing Nrf2 transcriptional activity. And PTEN deficiency caused an immune-suppressive microenvironment via up-regulating Keap1/Nrf2 pathway activity, which sequentially augments MHC I degradation. Finally, we found ML385, a novel Nrf2 inhibitor, significantly overcomes resistance to immunotherapy caused by PTEN deficiency.

Conclusions

In colorectal cancer, PTEN deficiency generates an immune-suppressive microenvironment that is poorly infiltrated with IFNγ+, Ki67+ and Gzmb+ T cells through hyperactivation of the Keap1/Nrf2 pathway. The Nrf2 inhibitor (ML385) is recognized as a promising therapy to overcome immune evasion driven by PTEN deficiency.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.