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

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.

Downregulation of PTCD1 in Bladder Urothelial Carcinoma Predicts Poor Prognosis and Levels of Immune Infiltration

“…e relationship between mutant genes and PTCD1 expression implies that PTCD1 may play a regulatory part in BLCA, which is needed to be validated by further studies. e tumor immune cell infiltration is of essential importance for the prognosis of bladder cancer and interferes the response to immunotherapy [50][51][52]. Several studies have demonstrated the importance of tumor-infiltrating immune cells and other immune molecules (including myeloid dendritic cell, T cell, neutrophil, and macrophage) in the prognosis of bladder cancer [53][54][55][56].…”

MHC I Expression Predicts Response to Checkpoint Inhibitors in Metastatic Urothelial Carcinoma but Lacks Prognostic Value in Localized Disease

“…Analyzing 149 patients with invasive urothelial carcinoma receiving a cystectomy in curative intent we deem the size and the homogeneity of our cohort as strengths of our study. Another trial has correlated MHC expression with survival in 77 patients, comprised of both invasive and non-invasive cancers, and did not find a clear association [14] Potential reasons why patients with MHC Ideficient tumors do not have a shortened survival are decreased inhibition of NK cells by reduced MHC expression [25] and the fact that loss of MHC I expression obviously does not confer a facilitation of metastatic tumor growth. All of our patients in cohort I still had localized disease and it will be of interest in the future to look for the prognostic relevance of MHC expression in metastatic patients as well as the evolution of MHC expression over time.…”

“…This is a hint is not necessarily an integral part of metastatic evolution but an earlier event. Looking at MHC loss it needs to be kept in mind that there are multiple ways of MHC I loss besides complete lack of expression, among others epigenetic downregulation, loss of allelic diversity and loss of beta2-microglobulin expression [14,23,26,27].…”

“…A better prognosis of patients with MHC I+ tumors has been shown in a plenty of tumor entities [12]. In bladder cancer there has been only one analysis published so far showing a trend to better outcome but lacking statistical significance because of the low number of patients [13,14]. It has been shown recently that a subset of human tumors atypically expresses MHC II, which is usually present on professional antigen-presenting cells like macrophages or dendritic cells to prime CD4 T cell responses.…”

Immunoprofiling: An Encouraging Method for Predictive Factors Examination in Lung Cancer Patients Treated with Immunotherapy

“…Mutations in the genes which encode molecules in the signaling pathways of tumor cells are probably responsible for a very strong suppression of the immune cells' influx into the neoplastic tissue [59,60]. Molecular abnormalities include incorrect activation of Wnt/β-catenin signaling pathways, which inhibits the tumor tissue infiltration with CD103-positive dendritic cells as well as causing loss of PTEN pathways' activating elements, which further inhibits cytotoxic T cells invasion [56,[59][60][61]. In this type of tumor, cancer cell antigens have been recognized, the specific immune response has been induced, but the extremely strong immunosuppressive tumor microenvironment (high concentration of tumor tissue metabolites: NO, IDO, and arginase) does not allow the immune cells to penetrate the neoplasm (Figure 4).…”