Tumor Escape Phenotype in Bladder Cancer Is Associated with Loss of HLA Class I Expression, T-Cell Exclusion and Stromal Changes.

Francisco Perea,Federico Garrido,Antonio Rodriguez-Nicolas,Hernani Gil-Julio,Angel Concha,Francisco Ruiz-Cabello,Natalia Aptsiauri,Jose Manuel Cozar,Amanda Rocío González-Ramirez

doi:10.3390/ijms22147248

Abstract

Cancer eradication and clinical outcome of immunotherapy depend on tumor cell immunogenicity, including HLA class I (HLA-I) and PD-L1 expression on malignant cells, and on the characteristics of the tumor microenvironment, such as tumor immune infiltration and stromal reaction. Loss of tumor HLA-I is a common mechanism of immune escape from cytotoxic T lymphocytes and is linked to cancer progression and resistance to immunotherapy with the inhibitors of PD-L1/PD-1 signaling. Here we observed that HLA-I loss in bladder tumors is associated with T cell exclusion and tumor encapsulation with stromal elements rich in FAP-positive cells. In addition, PD-L1 upregulation in HLA-I negative tumors demonstrated a correlation with high tumor grade and worse overall- and cancer-specific survival of the patients. These changes define common immuno-morphological signatures compatible with cancer immune escape and acquired resistance to therapeutic interventions across different types of malignancy. They also may contribute to the search of new targets for cancer treatment, such as FAP-expressing cancer-associated fibroblasts, in refractory bladder tumors.

Highlights

Tumor cell HLA class I (HLA-I) expression was evaluated in 131 bladder cancer tissue samples using immunohistological staining with monoclonal antibodies against HLA-ABC, distinct locus-specific monomorphic determinants and against beta2microglobulin gene (B2M)
In this work we demonstrated a strong association between the tumor loss of HLAI and the formation of a “non-permissive” tumor microenvironment characterized by reduced immune infiltration and strong stromal reaction with increased presence of fibroblast activation protein (FAP)+
We observed that HLA-I negative/PD-L1 positive phenotype has a significant correlation with high tumor grade and poor overall and cancer-specific survival

Summary

Introduction

The success of immune checkpoint inhibitors (ICI) depends, at least partially, on the expression of the maximum number of different HLA alleles, conferring a greater ability to present diverse tumor antigens to T cells [1,2,3] This antigen presentation and T-cell mediated tumor rejection is a common mechanism of anti-cancer immunity. Among the different known molecular mechanisms of HLA-I loss are mutations/chromosomal aberrations in beta2microglobulin gene (B2M), in HLA heavy chain genes and in the genes regulating IFNγ signaling pathways These alterations have been observed in a wide range of cancers and are likely to arise under the selective pressure imposed by the immune system [6,7,8,9,10,11]

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