TY - JOUR
T1 - Intravesical BCG in bladder cancer induces innate immune responses against SARS-CoV-2
AU - Pichler, Renate
AU - Diem, Gabriel
AU - Hackl, Hubert
AU - Koutník, Jiří
AU - Mertens, Laura S.
AU - D`Andrea, David
AU - Pradere, Benjamin
AU - Soria, Francesco
AU - Mari, Andrea
AU - Laukhtina, Ekaterina
AU - Krajewski, Wojciech
AU - Teoh, Jeremy Yuen-Chun
AU - del Guidice, Francesco
AU - Moschini, Marco
AU - the European Association of Urology-Young Academic Urologists (EAU-YAU): Urothelial carcinoma working group
AU - Thurnher, Martin
AU - Posch, Wilfried
N1 - Funding Information: This work was supported by the Austrian Science Fund (FWF; P34070-B13 to WP). JK receives DOC Fellowship from the Austrian Academy of Sciences. Funding Information: This work was supported by the Austrian Science Fund (FWF; P34070-B13 to WP). JK receives DOC Fellowship from the Austrian Academy of Sciences. Acknowledgments Publisher Copyright: Copyright © 2023 Pichler, Diem, Hackl, Koutník, Mertens, D`Andrea, Pradere, Soria, Mari, Laukhtina, Krajewski, Teoh, Del Guidice, Moschini, Thurnher and Posch.
PY - 2023
Y1 - 2023
N2 - BCG is the most efficient adjuvant therapy for high-risk, non-muscle-invasive bladder cancer (NMIBC). Both innate and adaptive immune responses have been implicated in BCG-mediated effects. BCG vaccination can boost innate immune responses via trained immunity (TI), resulting in an increased resistance to respiratory viral infections. Here we evaluated for the first time whether intravesical application of BCG triggers increased immunity against SARS-CoV-2 in patients with high-risk NMIBC. Serum and peripheral blood mononuclear cells (PBMCs) from heparinized whole blood samples of 11 unvaccinated SARS-CoV-2-naïve high-risk NMIBC patients were collected at baseline and during BCG treatment in a pre-COVID-19 era. To examine B-cell or T cell-dependent adaptive immunity against SARS-CoV-2, sera were tested for the presence of SARS-CoV-2 neutralizing antibodies. Using a SARS-CoV-2 peptide pool, virus-specific T cells were quantified via IFNγ ELISpot assays. To analyze innate immune responses, mRNA and protein expression levels of pro- and anti-inflammatory cytokines were measured after a 24-hour stimulation of PBMCs with either BCG or SARS-CoV-2 wildtype. ATAC- sequencing was performed to identify a potential epigenetic reprogramming in immune cells. We neither identified SARS-CoV-2 neutralizing antibodies nor SARS-CoV-2- reactive T cells, indicating that intravesical BCG did not induce adaptive immunity against SARS-CoV-2. However, a significant increase in mRNA as well as protein expression of IL-1β, IL-6 and TNFα, which are key cytokines of trained immunity, could be observed after at least four intravesical BCG instillations. Genomic regions in the proximity of TI genes (TLR2, IGF1R, AKT1, MTOR, MAPK14, HSP90AA1) were more accessible during BCG compared to baseline. Although intravesical BCG did not induce adaptive immune responses, repetitive intravesical instillations of BCG induced circulating innate immune cells that produce TI cytokines also in response to SARS-CoV-2.
AB - BCG is the most efficient adjuvant therapy for high-risk, non-muscle-invasive bladder cancer (NMIBC). Both innate and adaptive immune responses have been implicated in BCG-mediated effects. BCG vaccination can boost innate immune responses via trained immunity (TI), resulting in an increased resistance to respiratory viral infections. Here we evaluated for the first time whether intravesical application of BCG triggers increased immunity against SARS-CoV-2 in patients with high-risk NMIBC. Serum and peripheral blood mononuclear cells (PBMCs) from heparinized whole blood samples of 11 unvaccinated SARS-CoV-2-naïve high-risk NMIBC patients were collected at baseline and during BCG treatment in a pre-COVID-19 era. To examine B-cell or T cell-dependent adaptive immunity against SARS-CoV-2, sera were tested for the presence of SARS-CoV-2 neutralizing antibodies. Using a SARS-CoV-2 peptide pool, virus-specific T cells were quantified via IFNγ ELISpot assays. To analyze innate immune responses, mRNA and protein expression levels of pro- and anti-inflammatory cytokines were measured after a 24-hour stimulation of PBMCs with either BCG or SARS-CoV-2 wildtype. ATAC- sequencing was performed to identify a potential epigenetic reprogramming in immune cells. We neither identified SARS-CoV-2 neutralizing antibodies nor SARS-CoV-2- reactive T cells, indicating that intravesical BCG did not induce adaptive immunity against SARS-CoV-2. However, a significant increase in mRNA as well as protein expression of IL-1β, IL-6 and TNFα, which are key cytokines of trained immunity, could be observed after at least four intravesical BCG instillations. Genomic regions in the proximity of TI genes (TLR2, IGF1R, AKT1, MTOR, MAPK14, HSP90AA1) were more accessible during BCG compared to baseline. Although intravesical BCG did not induce adaptive immune responses, repetitive intravesical instillations of BCG induced circulating innate immune cells that produce TI cytokines also in response to SARS-CoV-2.
KW - BCG
KW - COVID-19
KW - SARS-CoV-2
KW - bladder cancer
KW - trained immunity
KW - viral infections
UR - http://www.scopus.com/inward/record.url?scp=85165929372&partnerID=8YFLogxK
U2 - https://doi.org/10.3389/fimmu.2023.1202157
DO - https://doi.org/10.3389/fimmu.2023.1202157
M3 - Article
C2 - 37520557
SN - 1664-3224
VL - 14
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 1202157
ER -