Clinical Significance and Therapeutic Potential of the Programmed Death-1 Ligand/Programmed Death-1 Pathway in Human Pancreatic Cancer

Abstract

Purpose:The programmed death-1ligand/programmed death-1 (PD-L/PD-1) pathway has been recently suggested to play a pivotal role in the immune evasion of tumors from host immune system. In this study, we tried to reveal the clinical importance and therapeutic potential of the PD-L/ PD-1pathway in pancreatic cancer, which is one of the most aggressive and intractable malignant tumors. Experimental Design: We used immunohistochemistry to investigate PD-L expression in 51 patients with pancreatic cancer who underwent surgery and explored the therapeutic efficacy of blocking the PD-L1/PD-1pathway in murine pancreatic cancer in vivo. Results: PD-L1^positive patients had a significantly poorer prognosis than the PD-L1^negative patients, whereas there was no significant correlation of tumor PD-L2 expression with patient survival. PD-L1 expression was inversely correlated with tumor-infiltrating T lymphocytes, particularly CD8 + T cells. These clinical data have suggested that the PD-L1/PD-1 pathway may be a critical regulator in human pancreatic cancer. Monoclonal antibodies against PD-L1 or PD-1 induced a substantial antitumor effect on murine pancreatic cancer in vivo. PD-L1 blockade promoted CD8 + T-cell infiltration into the tumor and induced local immune activation. Furthermore, the combination of anti^PD-L1 monoclonal antibody and gemcitabine exhibited a significant synergistic effect on murine pancreatic cancer and resulted in complete response without overt toxicity. Conclusion: Our data suggest for the first time that PD-L1 status may be a new predictor of prognosis for patients with pancreatic cancer and provide the rationale for developing a novel therapy of targeting the PD-L/PD-1pathway against this fatal disease.

Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in colorectal cancer: Relationship with sidedness and prognosis

“…32-34 Nonetheless, an abundance of studies have reported high PD-L1 expression to be associated with an impaired prognosis due to induction of immune evasion, 6 , 7 , 35 being the rationale for PD-1/PD-L1 blockade. 36 , 37 Noteworthy, a significant part of studies regarding the prognostic impact of PD-L1 have not discriminated between its expression in tumour cells and tumour-infiltrating immune cells.…”

“…5 Indeed, expression of PD-L1 on tumour cells has been found to suppress CD8 + T cell activity and to be associated with an impaired prognosis is several types of solid cancer. 6-8 …”

Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer

“…Perhaps this difference in cytokine production is due to the fact that PD-1 typically has greater effects on cytokine production than on cellular proliferation, with significant effects on IFN-c, tumor-necrosis factora and IL-2 production. 21 Another possible explanation is that, in addition to PD-1 upregulation in CD8 1 T cells, higher PD-L1 expression in tumor cells [16][17][18] not in PBMCs, may also have contributed to impaired CD8 1 T-cell function. As a result, it is possible that the PD-1/PD-L1 pathway may have greater effects on CD8 1 T cells in a tumor setting than on peripheral blood CD8 1 T cells.…”

“…[6][7][8][9] Involvement of the PD-1 pathway has also been shown during hepatitis B and C virus infection [10][11][12][13] with PD-L1 expression demonstrated in situ on a wide variety of solid tumors including pancreas, lung, ovarian and bladder tumors. [14][15][16][17][18] Studies relating PD-L1 expression on tumors to disease outcome show that PD-L1 expression strongly correlates with unfavorable prognosis in kidney, bladder, gastric and pancreatic cancer. [16][17][18] Such studies indicate that the PD-1/PD-L1 pathway may also play a role in tumor immunity.…”

“…[14][15][16][17][18] Studies relating PD-L1 expression on tumors to disease outcome show that PD-L1 expression strongly correlates with unfavorable prognosis in kidney, bladder, gastric and pancreatic cancer. [16][17][18] Such studies indicate that the PD-1/PD-L1 pathway may also play a role in tumor immunity.…”