Abstract：Overexpression of immune checkpoint molecules suppresses tumor-specific T cell immunity in the cancer microenvironment, contributes to tumor immune escape and promotes tumor progression and metastasis. Programmed death-1 (PD-1) and its ligand (PD-L1) are two of immune checkpoint molecules that have been studied profoundly, and currently increasing clinical trials demonstrated that PD-1 and PD-L1 inhibitors turned out to be beneficial and safe for urologic malignancies. Here, we update the progression of PD-1/PD-L1 inhibitors in the treatment of urologic malignancies.
[1] Chen WQ, Zheng RS, Peter D, et al. Cancer Statistics in China, 2015. CA Cancer J Clin, 2016,66(2):115-132. [2] 林城,陈雄,刘静南,等.PD-1/PD-L1信号通路在非小细胞肺癌免疫逃逸及其治疗中的研究进展.中国肺癌杂志,2014,17(10):734-740. [3] Rixe O, Bukowski RM, Michaelson MD, et al. Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer, a phase II study. Lancet Oncol, 2007,8(11):975-984 [4] Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol, 2004, 22:329-360. [5] Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer, 2012,12(4):252-264. [6] Ishida Y, Agata Y, Shibahara K, et al. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J, 1992,11(11):3887-3895. [7] Yamazaki T, Akiba H, Iwai H, et al. Expression of programmed death 1 ligands by murine T cells and APC. J Immunol, 2002,169(10):5538-5545. [8] Dong H, Zhu G, Tamada K, et al. B7-H1, a third member of the B7 family, cositimulates T cell proliferation and interlukin-10 secretion. Nat Med, 1999,5(12):1365-1369. [9] Intlekofer AM, Thompson CB. At the bench, preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy. J Leukoc Biol, 2013,94(1):25-39. [10] Taube JM, Klein A, Brahmer JR, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res, 2014,20(19):5064-5074. [11] Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, et al. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med, 2012,209(6):1201-1217. [12] Carter L, Fouser LA, Jussif J, et al. PD-1, PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2. Eur J Immunol, 2002,32(3):634-643. [13] Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol, 2008,26:677-704. [14] Nishimura H, Nose M, Hiai H, et al. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity, 1999,11(2):141-151. [15] Zhang J, Braun MY. PD-1 deletion restores susceptibility to experimental autoimmune encephalomyelitis in miR-155-deficient mice. Int Immunol, 2014,26(7):407-415. [16] Ding H, Wu X, Wu J, et al. Delivering PD-1 inhibitory signal concomitant with blocking ICOS co-stimulation suppresses lupus-like syndrome in autoimmune BXSB mice. Clin Immunol, 2006,118(2-3):258-267. [17] Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis, a potential mechanism of immune evasion. Nat Med, 2002,8(8):793-800. [18] Cao Y, Zhang L, Kamimura Y, et al. B7-H1 overexpression regulates epithelial-mesenchymal transition and accelerates carcinogenesis in skin. Cancer Res, 2011,71(4):1235-1243. [19] Thompson RH, Kwon ED. Significance of B7-H1 overexpression in kidney cancer. Clin Genitourin Cancer, 2006,5(3):206-211. [20] Frigola X, Inman BA, Lohse CM, et al. Identification of a soluble form of B7-H1 that retains immunosuppressive activity and is associated with aggressive renal cell carcinoma. Clin Cancer Res, 2011,17(7):1915-1923. [21] Thompson RH, Kuntz SM, Leibovich BC, et al. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res, 2001,66(7):3381-3385. [22] Huang Y, Zhang SD, McCrudden C, et al. The prognostic significance of PD-L1 in bladder cancer. Oncol Rep, 2015,33(6):3075-3084. [23] Gevensleben H, Dietrich D, Golletz C, et al. The Immune Checkpoint Regulator PD-L1 Is Highly Expressed in Aggressive Primary Prostate Cancer. Clin Cancer Res, 2016,22(8):1969-1977. [24] Goltz D, Holmes EE, Gevensleben H, et al. CXCL12 promoter methylation and PD-L1 expression as prognostic biomarkers in prostate cancer patients. Oncotarget. Oncotarget, 2016,7(33):53309-53320 [25] Gevensleben H, Holmes EE, Goltz D, et al. PD-L1 promoter methylation is a prognostic biomarker for biochemical recurrence-free survival in prostate cancer patients following radical prostatectomy. Oncotarget, 2016,7(48):79943-79955 [26] Iwai Y, Ishida M, Tanaka Y, et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A, 2002,99(19):12293-12297. [27] Zang X, Allison JP. The B7 family and cancer therapy, costimulation and coinhibition. Clin. Cancer Res, 2007,13(18 Pt 1):5271-5279. [28] John LB, Devaud C, Duong CP, et al. Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin Cancer Res, 2013,19(20):5636-5646. [29] Ding ZC, Lu X, Yu M, et al. Immunosuppressive myeloid cells induced by chemotherapy attenuate antitumor CD4+ T-Cell responses through the PD-1-PD-L1 Axis. Cancer Res, 2014,74(13):3441-3453. [30] Deng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest, 2014,124(2):687-695. [31] Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent antiprogrammed death-1 (MDX-1106) in refractory solid tumors, safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol, 2010,28(19):3167-3175. [32] Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med, 2015,373(19):1803-1813. [33] Amin A, Plimack ER, Infante JR, et al. Nivolumab (anti-PD-1, BMS-936558, ONO-4538) in combination with sunitinib or pazopanib in patients(pts) with metastatic renal cell carcinoma (mRCC). 2014 ASCO Annual Meeting. BJU Int, 2014,114(Suppl 4):2. [34] Hammers HJ, Plimack ER, Infante JR, et al. Expanded cohort results from CheckMate 016, a phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC). 2015 ASCO Annual Meeting. J Clin Oncol, 2015,33(15_suppl):4516. [35] Atkins MB, Choueiri T, Hodi SF, et al. Pembrolizumab (MK-3475) plus low-dose ipilimumab (IPI) in patients (pts) with advanced melanoma (MEL) or renal cell carcinoma (RCC): data from the KEYNOTE-029 phase 1 study. 2015 ASCO Annual Meeting, J Clin Oncol, 2015,33(15_suppl):3009. [36] McDermott DF, Sosman JA, Sznol M, et al. Atezolizumab, an antiprogrammed death-ligand 1 antibody, in metastatic renal cell carcinoma, long-term safety, clinical activity, and immune correlates from a phase Ia study. J Clin Oncol, 2016,34(8):833-842. [37] Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy, a single-arm, multicentre, phase 2 trial. Lancet, 2016,387(10031):1909-1920. [38] Massard C, Gordon MS, Sharma S, et al. Safety and Efficacy of Durvalumab (MEDI4736): an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With Advanced Urothelial Bladder Cancer. J Clin Oncol, 2016,34(26):3119-3125. [39] Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med, 2012,366(26):2443-2454.
