José Francisco Flores-Martín1,2,3, Francisco Perea4, Manuela Exposito-Ruiz5,6, Francisco Javier Carretero5,4, Teresa Rodriguez5,4, Marina Villamediana4,7, Francisco Ruiz-Cabello5,4,7, Federico Garrido5,4,7, José Manuel Cózar-Olmo5,8, Natalia Aptsiauri5,4. 1. Instituto de Investigación Biosanitaria (ibs.GRANADA), Granada, Spain. josefloresmartin@gmail.com. 2. Unidad de Gestión Clínica de Urología, Hospital Universitario Virgen de las Nieves de Granada, Granada, Spain. josefloresmartin@gmail.com. 3. Unidad de Gestión Clínica de Urología, Complejo Hospitalario Universitario de Jaén, Jaén, Spain. josefloresmartin@gmail.com. 4. Departamento de Bioquímica, Biología Molecular e Inmunología III, Facultad de Medicina, Universidad de Granada, Granada, Spain. 5. Instituto de Investigación Biosanitaria (ibs.GRANADA), Granada, Spain. 6. Fundación para la Investigación Biosanitaria de Andalucía Oriental (FIBAO), Granada, Spain. 7. Unidad de Laboratorio Clínico, Hospital Universitario Virgen de las Nieves, Granada, Spain. 8. Unidad de Gestión Clínica de Urología, Hospital Universitario Virgen de las Nieves de Granada, Granada, Spain.
Abstract
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.
BACKGROUND:Tumorhuman 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.