A Combination of Positive Tumor HLA-I and Negative PD-L1 Expression Provides an Immune Rejection Mechanism in Bladder Cancer.

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.

Frequent HLA class I alterations in human prostate cancer: molecular mechanisms and clinical relevance.

Reduced expression of HLA class I is an important immune escape mechanism from cytotoxic T cells described in various types of malignancy. It often correlates with poor prognosis and resistance to therapy. However, current knowledge about the frequency, underlying molecular mechanisms, and prognostic value of HLA class I and II alterations in prostate cancer (PC) is limited. Immunohistochemical analysis demonstrated that 88 % of the 42 studied cryopreserved prostate tumors have at least one type of HLA alteration as compared to adjacent normal prostate epithelium or benign hyperplasia. Total loss of HLA-I expression found in 50 % of tumors showed an association with increased incidence of tumor relapse, perineural invasion, and high D'Amico risk. The remaining HLA-I-positive tumors demonstrated locus and allelic losses detected in 26 and 12 % of samples, respectively. Loss of heterozygosity at chromosome 6 was detected in 32 % of the studied tumors. Molecular analysis revealed a reduced expression of B2M, TAP2, tapasin and NLRC5 mRNA in microdissected HLA-I-negative tumors. Analysis of twelve previously unreported cell lines derived from neoplastic and normal epithelium of cancerous prostate revealed different types of HLA-I aberration, ranging from locus and/or allelic downregulation to a total absence of HLA-I expression. The high incidence of HLA-I loss observed in PC, caused by both regulatory and structural defects, is associated with more aggressive disease development and may pose a real threat to patient health by increasing cancer progression and resistance to T-cell-based immunotherapy.