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Proteasomal processing immune escape mechanisms in platinum-treated advanced bladder cancer
- In recent years, the number and type of treatment options in advanced bladder cancer (BC) have been rapidly evolving. To select an effective therapy and spare unnecessary side effects, predictive biomarkers are urgently needed. As the host’s anti-cancer immune response is by far the most effective system to impede malignant tumor growth, immune system-based biomarkers are promising. We have recently described altered proteasomal epitope processing as an effective immune escape mechanism to impair cytotoxic T-cell activity. By altering the neoantigens’ characteristics through different proteasomal peptide cleavage induced by non-synonymous somatic mutations, the ability for T-cell activation was decreased (“processing escapes”). In the present study, we analyzed primary chemo-naïve tissue samples of 26 adjuvant platinum-treated urothelial BC patients using a targeted next-generation sequencing panel followed by the epitope determination of affected genes, a machine-learning based prediction of epitope processing and proteasomal cleavage and of HLA-affinity as well as immune activation. Immune infiltration (immunohistochemistries for CD8, granzyme B, CD45/LCA) was digitally quantified by a pathologist and clinico-pathological and survival data were collected. We detected 145 epitopes with characteristics of a processing escape associated with a higher number of CD8-positive but lower number of granzyme B-positive cells and no association with PD-L1-expression. In addition, a high prevalence of processing escapes was associated with unfavorable overall survival. Our data indicate the presence of processing escapes in advanced BC, potentially creating a tumor-promoting pro-inflammatory environment with lowered anti-cancerous activity and independence from PD-L1-expression. The data also need to be prospectively validated in BC treated with immune therapy.
Author: | Michael WessollyORCiDGND, Fabian Dominik MairingerORCiDGND, Thomas HeroldGND, Boris HadaschikORCiDGND, Tibor SzarvasORCiDGND, Henning ReisORCiDGND |
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URN: | urn:nbn:de:hebis:30:3-831623 |
DOI: | https://doi.org/10.3390/genes13030422 |
ISSN: | 2073-4425 |
Parent Title (English): | Genes |
Publisher: | MDPI |
Place of publication: | Basel |
Document Type: | Article |
Language: | English |
Date of Publication (online): | 2022/02/25 |
Date of first Publication: | 2022/02/25 |
Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Release Date: | 2024/05/07 |
Tag: | bladder cancer; immune therapy; immunohistochemistry; platinum-based chemotherapy; proteasomal processing escape; proteasome; urothelial carcinoma |
Volume: | 13 |
Issue: | 3, art. 422 |
Article Number: | 422 |
Page Number: | 12 |
First Page: | 1 |
Last Page: | 12 |
Note: | This work was funded by the Wilhelm Sander-Stiftung (grant number: D/106-22012). T.S. was supported by a János Bolyai Research Scholarship of the Hungarian Academy of Sciences. Supported by the ÚNKP-20-5-SE-1 New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research Development and Innovation Fund. |
HeBIS-PPN: | 521124093 |
Institutes: | Medizin |
Dewey Decimal Classification: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit | |
Sammlungen: | Universitätspublikationen |
Licence (German): | ![]() |