55P - DPP9 promotes renal cancer PD-L1 expression through SHMT2-BRISC complex

Background

In recent years, immunotherapy has attracted much attention in the treatment of kidney cancer. Immune checkpoints, especially PD-L1, play an important role in the treatment of kidney cancer. Therefore, the treatment of immune-infiltration and immunosuppression through immune checkpoints has become an important direction in treating renal cancer.

Methods

Several high DPP9 expression and low DPP9 expression tumor tissues were selected for single-cell sequencing. Results told us that DPP9 regulates T-cell infiltrating and transcription of PD-L1. We used co-IP assay to discover the interaction between DPP9 and SHMT2-BRISC. Then we established the overexpression/knockout DPP9 renal cell lines to detect the upstream signal pathway of PD-L1, co-cultured with PBMC cells to observe the influence of immune escape. Meanwhile, we used organoids to confirm the above experiments. Finally, we used DPP9 inhibitor and PD-L1 monoclonal antibody in animal experiments.

Results

Single-cell sequencing showed that T-cell exhaustion signal was significantly up-regulated in the group with high DPP9 expression. IHC staining of DPP9, PD-L1, CD3, PD-1 in kidney cancer section was verified. Overexpression/knocked out of DPP9 in kidney cancer cells such as 786-O, 769P, caki-1 showed that DPP9 could regulate the transcription and translation of PD-L1. Then co-IP showed that DPP9 interacted with SHMT2, BRE, FAM175B proteins in the BRISC complex. The binding level of DPP9 and SHMT2-BRISC complex in the presence or absence of IFN-γ was detected, and dynamic binding was sought to determine whether more FAM175B and SHMT2 were involved in the formation of complex in the presence of DPP9, thus regulating the transcription of PD-L1 in the condition of IFN-γ. PD-L1 monoclonal antibody can inhibit the immune escape of renal cancer induced by DPP9, and the effect is better when combined with DPP9 inhibitors.

Conclusions

DPP9 can up-regulate the expression of PD-L1 in renal cancer cells through dynamically adjusting the stability of the BRISC complex via SHMT2. We provide the clinical principle and mechanism of DPP9 inhibitor combined with PD-L1 monoclonal antibody, and further determine the patient population suitable for immunotherapy.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.