Presentation Authors: Yuji Sagara*, Yasuyoshi Miyata, Kyohei Araki, Yuichirou Nakamura, Takuji Yasuda, Tomohiro Matsuo, Kojiro Ohba, Hideki Sakai, Nagasaki, Japan
Introduction: The programmed death ligand 1 (PD-L1) plays crucial roles for the modulation of immune responses under physiological conditions. However, in malignant cells, activation of the PD-L1 participates in immune evasion, and its over-expression was significantly associated with malignant aggressiveness in various types of malignancies including upper tract urothelial carcinoma (UTUC). In addition to such immune responses, PD-L1 is also reported to regulate other cancer-related activities such as cell proliferation, invasion, and angiogenesis. The main aim is to investigate PD-L1 expression and these pathological activities in patients with UTUC.
Methods: Expressions of PD-L1 were examined immunohistochemically in 152 UTUC specimens that obtained by radical operation. We also investigated cancer cell proliferation index (PI; used by anti-Ki-67 antibody), micro-vessel density (MVD; by anti-CD105 antibody), and expressions of matrix metalloproteinase (MMP)-2 and -9, cyclooxygenase (COX)-2, and vascular endothelial growth factor (VEGF)-A. When PD-L1 immunoreactivity was detected in â‰¥5% of cancer cells, it was judged as positive expression.
Results: PD-L1 expression was judged as positive in 39 specimens (25.7%), and it was significantly associated with grade (P = 0.043) and pT stage (P = 0.021), but not presence of lymph node metastasis (P = 0.184). Mean / SD of MVD in PD-L1-positive specimens (63.9 / 19.9 / mm2) were significantly higher (P = 0.009) than that in negative one (54.4 / 18.2). Similar trend was also found in PI (P = 0.002). In regard to cancer-related molecules, PD-L1 expression significantly correlated with expressions of VEGF-A (P < 0.001), MMP-2 (P = 0.026), and MMP-9 (P = 0.042), but not with COX-2 (P = 0.228). Furthermore, multi-variate analysis model including pathological features demonstrated that PD-L1 expression was independently associated with VEGF-A expression (hazard ratio = 7.7, 95% confidential interval = 2.6-22.7, P < 0.001), but not with expressions of MMP-2 or MMP-9. In addition, VEGF-A expression positively correlated to MVD (r = 0.39, P < 0.001) and PI (r = 0.38, P < 0.01).
Conclusions: Our results demonstrated that PD-L1 expression was closely associated tumor growth via regulation of cancer cell proliferation and angiogenesis. In addition, VEGF-A regulated by PD-L1 was speculated to play important roles for such pathological mechanism