PD-L1 is a direct target of cancer-FOXP3 in pancreatic ductal adenocarcinoma (PDAC), and combined immunotherapy with antibodies against PD-L1 and CCL5 is effective in the treatment of PDAC

Abstract

High expression of PD-L1 marks the poor prognosis of pancreatic ductal adenocarcinomas (PDAC). However, the regulatory mechanism of PD-L1 remains elusive. We recently reported that cancer Forkhead box protein 3 (Cancer-FOXP3 or C-FOXP3) promoted immune evasion of PDAC by recruiting Treg cells into PDAC via upregulation of CCL5. In this study, we confirmed that PD-L1 was overexpressed in PDAC samples from two independent cohorts of patients with radical resection. Moreover, C-FOXP3 was colocalized and correlated with the expression of PD-L1 in tumor cells at the mRNA and protein levels, and this finding was confirmed by the The Cancer Genome Atlas (TCGA) database. Chromatin immunoprecipitation (ChIP) revealed that C-FOXP3 directly bound to the promoter region of PD-L1 in pancreatic cancer cells. Furthermore, overexpression of C-FOXP3 activated the luciferase reporter gene under the control of the PD-L1 promoter. However, mutation of the binding motif-a completely reversed the luciferase activity. In addition, C-FOXP3-induced upregulation of PD-L1 effectively inhibited the activity of CD8 + T cells. Based on our recent finding that the CCL-5 antibody achieved a better response to PDAC models with high C-FOXP3 levels, we further demonstrated that the PD-L1 antibody strengthened the antitumor effect of CCL-5 blockade in xenograft and orthotopic mouse models with high C-FOXP3 levels. In conclusion, C-FOXP3 directly activates PD-L1 and represents a core transcription factor that mediates the immune escape of PDAC. Combined blockade of PD-L1 and CCL-5 may provide an effective therapy for patients with PDAC that have high C-FOXP3 levels.

The Role of S100A9 in the Interaction Between Pancreatic Ductal Adenocarcinoma Cells and Stromal Cells

“…In many cancers, the interaction of costimulatory molecules on T lymphocytes with the tumor-associated membrane-bound protein PD-L1 can lead to apoptosis of activated T cells. Tumor-associated PD-L1 expression was reported to increase the apoptosis of activated T lymphocytes and assist cancer cells in escaping immune surveillance [30,46]. High expression of PD-L1 in pancreatic cancers is associated with a poor prognosis [24].…”

“…In addition to its chemotactic effect, S100A9 has been reported to be the endogenous ligand of Toll-like receptor 4 (TLR4) and to induce surface expression of PD-L1 in primary hematopoietic cells [28,29]. High expression of PD-L1 in PDAC was associated with poor prognosis [30]; however, the mechanism that regulates the expression of PD-L1 in PDAC is not clear. To verify the effect of S100A9 on the expression of PD-L1 on monocytes, we treated U937 cells with interferon gamma (IFN-γ)along with recombinant S100A9 and detected the surface expression of PD-L1 with flow cytometry.…”

Overview of current targeted therapy in gallbladder cancer

“…Elevated PD-L1/PD-1 levels were correlated with poor survival of cancer patients with NSCLC, 230 melanoma, 231 gastric cancer, 232 adrenocortical carcinoma, 233 breast cancer, 234 hepatic cancer, 235 and pancreatic cancer. 236,237 Specifically, PD-L1 expression in GBC (23%) was comparable to breast cancer (23%), urothelial cancer (20%), and pulmonary squamous cell carcinoma (27%). 238,239 Mody et al 240 found that 12% patients with tumor cell-expressing PD-L1 and 55% patients with tumor-infiltrating lymphocyte (TIL)-expressing PD-1 in a total of 203 GBC patients were associated with corresponding genetic aberrations and tumor mutational burden (TMB) status.…”

Inflammation-Driven Breast Tumor Cell Plasticity: Stemness/EMT, Therapy Resistance and Dormancy

“…In this context, measures that combine efforts to reduce inflammation and in parallel strengthen anti-tumor immune activities ( e.g. , immunotherapies) (as exemplified in ( 140 – 145 )), may have an even greater benefit in the clinic. This approach, that tilts the immune balance by down-regulating inflammation and increasing protective immunity, is practically feasible.…”