Loss of tumor intrinsic PD-L1 confers resistance to drug-induced apoptosis in human colon cancer

Rok, strany: 2021, 144 - 153

Colorectal cancer (CRC) with BRAF (V600E) is associated with microsatellite instability (MSI) that predicts response to immune checkpoint inhibitors. We demonstrated the interrogation of TCGA RNA-seq human datasets revealed that BRAFV600E tumors had significantly higher Programmed Death Ligand 1 (PD-L1) mRNA compared to non-mutated BRAF CRCs. Also, MSI-H tumors were evaluated as higher PD-L1 than MSS CRCs. Inhibition of MEK/ERK by cobimetinib or CDK inhibitor dinaciclib was shown to attenuate mutant BRAF-induced PD-L1 coincident with reduced c-JUN and YAP expression whose combined knockdown reduced PD-L1. Using TCGA datasets, PD-L1 mRNA expression in human colon cancers was significantly associated with YAP expression. The deletion of PD-L1 can reduce tumor cell growth shown by clonogenic assay. Analysis of the role of PD-L1 as a mediator of chemosensitivity was then performed. Knockout of PD-L1 was shown to attenuate the induction of DNA double-strand breaks (pH2AX) and caspase-3 cleavage by 5-fluorouracil (5-FU) and paclitaxel compared to parental CRC cells. Results were confirmed in PD-L1 knockout MC38 murine CRC cells where re-expression of wild-type PD-L1 promoted DNA damage and apoptosis. We also performed the clonogenic assay and flow cytometry to prove that loss of PD-L1 attenuated DNA damage and apoptosis induced by diverse anti-cancer drugs that could be reversed by restoration of wild-type PD-L1. Mechanistically, knockout of PD-L1 reduced chemosensitivity in association with reductions in p-AKT and in BH3-only proteins BIM and BIK, rather than STAT3 in CRC cells. However, STAT3 had a significant role in melanoma, which shows the heterogeneity of cancers. In summary, BRAFV600E can upregulate PD-L1 expression that was induced by c-jun and YAP to enhance chemotherapy-induced apoptosis. Together, we demonstrate a potential role for PD-L1 as a regulator of chemotherapy-induced apoptosis whose deletion or suppression confers chemoresistance. These findings expand the understanding of PD-L1 functions to include nonimmune mechanisms and suggest the potential use of PD-L1 as a biomarker of response to cytotoxic chemotherapy.

ISO 690:

Feng, D., Chen, Z., He, X., Huang, S., Zhang, Z. 2021. Loss of tumor intrinsic PD-L1 confers resistance to drug-induced apoptosis in human colon cancer. In NEOPLASMA, vol. 68, no.1, pp. 144-153. 0028-2685. DOI: https://doi.org/10.4149/neo_2020_200531N589

APA:

Feng, D., Chen, Z., He, X., Huang, S., Zhang, Z. (2021). Loss of tumor intrinsic PD-L1 confers resistance to drug-induced apoptosis in human colon cancer. NEOPLASMA, 68(1), 144-153. 0028-2685. DOI: https://doi.org/10.4149/neo_2020_200531N589

Vydavateľ: AEPress, Ltd.