PMID- 31011905 OWN - NLM STAT- MEDLINE DCOM- 20191218 LR - 20191218 IS - 1534-4681 (Electronic) IS - 1068-9265 (Linking) VI - 26 IP - 8 DP - 2019 Aug TI - A Combination of Positive Tumor HLA-I and Negative PD-L1 Expression Provides an Immune Rejection Mechanism in Bladder Cancer. PG - 2631-2639 LID - 10.1245/s10434-019-07371-2 [doi] AB - BACKGROUND: Tumor human leukocyte antigen class I (HLA-I) expression plays an important role in T cell-mediated tumor rejection. Loss of HLA-I is associated with cancer progression and resistance to immunotherapy, including antibodies blocking programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) signaling. Our objective was to analyze a correlation between HLA-I, tumor immune infiltration, and PD-L1/PD-1 axis in bladder cancer in association with the clinicopathologic features of patients. METHODS: We analyzed 85 cryopreserved bladder tumors by immunohistochemistry to investigate the expression of HLA-I, PD-L1, PD-1, CD3, CD8, and CXC chemokine receptor 4 (CXCR4). The results were correlated with tumor stage and other clinicopathologic variables of patients. RESULTS: We found a strong positive correlation between tumor HLA-I expression and infiltration with CD3+ and CD8 + T cells. PD-L1 expression was positive in 15.5% of tumors and heterogeneous in 40.5%, and was linked to a more advanced tumor stage. The majority of HLA-I-positive/heterogeneous tumors also expressed PD-L1 and PD-1, which were significantly correlated with each other and with lymphocyte infiltration. Interestingly, the analysis of the simultaneous expression of both markers revealed that 85.2% of tumors with a positive/heterogeneous HLA-I phenotype and negative for PD-L1 were mostly non-invasive, representing a 'tumor rejection' immune phenotype. CONCLUSIONS: High tumor HLA-I expression with absence of PD-L1 provides bladder cancer with an immune rejection mechanism. Evaluation of PD-L1 and HLA-I together should be considered in bladder cancer and may provide a new predictive biomarker of tumor invasiveness and of the response to 'immune checkpoint' therapy. FAU - Flores-Martin, Jose Francisco AU - Flores-Martin JF AD - Instituto de Investigacion Biosanitaria (ibs.GRANADA), Granada, Spain. josefloresmartin@gmail.com. AD - Unidad de Gestion Clinica de Urologia, Hospital Universitario Virgen de las Nieves de Granada, Granada, Spain. josefloresmartin@gmail.com. AD - Unidad de Gestion Clinica de Urologia, Complejo Hospitalario Universitario de Jaen, Jaen, Spain. josefloresmartin@gmail.com. FAU - Perea, Francisco AU - Perea F AD - Departamento de Bioquimica, Biologia Molecular e Inmunologia III, Facultad de Medicina, Universidad de Granada, Granada, Spain. FAU - Exposito-Ruiz, Manuela AU - Exposito-Ruiz M AD - Instituto de Investigacion Biosanitaria (ibs.GRANADA), Granada, Spain. AD - Fundacion para la Investigacion Biosanitaria de Andalucia Oriental (FIBAO), Granada, Spain. FAU - Carretero, Francisco Javier AU - Carretero FJ AD - Instituto de Investigacion Biosanitaria (ibs.GRANADA), Granada, Spain. AD - Departamento de Bioquimica, Biologia Molecular e Inmunologia III, Facultad de Medicina, Universidad de Granada, Granada, Spain. FAU - Rodriguez, Teresa AU - Rodriguez T AD - Instituto de Investigacion Biosanitaria (ibs.GRANADA), Granada, Spain. AD - Departamento de Bioquimica, Biologia Molecular e Inmunologia III, Facultad de Medicina, Universidad de Granada, Granada, Spain. FAU - Villamediana, Marina AU - Villamediana M AD - Departamento de Bioquimica, Biologia Molecular e Inmunologia III, Facultad de Medicina, Universidad de Granada, Granada, Spain. AD - Unidad de Laboratorio Clinico, Hospital Universitario Virgen de las Nieves, Granada, Spain. FAU - Ruiz-Cabello, Francisco AU - Ruiz-Cabello F AD - Instituto de Investigacion Biosanitaria (ibs.GRANADA), Granada, Spain. AD - Departamento de Bioquimica, Biologia Molecular e Inmunologia III, Facultad de Medicina, Universidad de Granada, Granada, Spain. AD - Unidad de Laboratorio Clinico, Hospital Universitario Virgen de las Nieves, Granada, Spain. FAU - Garrido, Federico AU - Garrido F AD - Instituto de Investigacion Biosanitaria (ibs.GRANADA), Granada, Spain. AD - Departamento de Bioquimica, Biologia Molecular e Inmunologia III, Facultad de Medicina, Universidad de Granada, Granada, Spain. AD - Unidad de Laboratorio Clinico, Hospital Universitario Virgen de las Nieves, Granada, Spain. FAU - Cozar-Olmo, Jose Manuel AU - Cozar-Olmo JM AD - Instituto de Investigacion Biosanitaria (ibs.GRANADA), Granada, Spain. AD - Unidad de Gestion Clinica de Urologia, Hospital Universitario Virgen de las Nieves de Granada, Granada, Spain. FAU - Aptsiauri, Natalia AU - Aptsiauri N AD - Instituto de Investigacion Biosanitaria (ibs.GRANADA), Granada, Spain. AD - Departamento de Bioquimica, Biologia Molecular e Inmunologia III, Facultad de Medicina, Universidad de Granada, Granada, Spain. LA - eng GR - PI12/02031/Instituto de Salud Carlos III/ GR - PI11/01022/Instituto de Salud Carlos III/ GR - PI11/01386/Instituto de Salud Carlos III/ GR - RETIC RD 06/02/Instituto de Salud Carlos III/ GR - Group CTS-143/Junta de Andalucia/ PT - Journal Article DEP - 20190422 PL - United States TA - Ann Surg Oncol JT - Annals of surgical oncology JID - 9420840 RN - 0 (B7-H1 Antigen) RN - 0 (Biomarkers, Tumor) RN - 0 (CD274 protein, human) RN - 0 (Histocompatibility Antigens Class I) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - B7-H1 Antigen/immunology/*metabolism MH - Biomarkers, Tumor/metabolism MH - CD8-Positive T-Lymphocytes/*immunology/metabolism/pathology MH - Female MH - Follow-Up Studies MH - Histocompatibility Antigens Class I/immunology/*metabolism MH - Humans MH - Lymphatic Metastasis MH - Lymphocytes, Tumor-Infiltrating/*immunology/metabolism/pathology MH - Male MH - Middle Aged MH - Muscle Neoplasms/*immunology/metabolism/pathology/surgery MH - Neoplasm Recurrence, Local/*immunology/metabolism/pathology/surgery MH - Prognosis MH - Tumor Microenvironment MH - Urinary Bladder Neoplasms/*immunology/metabolism/pathology/surgery EDAT- 2019/04/24 06:00 MHDA- 2019/12/19 06:00 CRDT- 2019/04/24 06:00 PHST- 2018/08/21 00:00 [received] PHST- 2019/04/24 06:00 [pubmed] PHST- 2019/12/19 06:00 [medline] PHST- 2019/04/24 06:00 [entrez] AID - 10.1245/s10434-019-07371-2 [pii] AID - 10.1245/s10434-019-07371-2 [doi] PST - ppublish SO - Ann Surg Oncol. 2019 Aug;26(8):2631-2639. doi: 10.1245/s10434-019-07371-2. Epub 2019 Apr 22.