Intravesical BCG in patients with non-muscle invasive bladder cancer induces trained immunity and decreases respiratory infections

Jelmer H. Van Puffelen; Boris Novakovic; Liesbeth Van Emst; Denise Kooper; Tahlita C.M. Zuiverloon; Ursula T.H. Oldenhof; J. Alfred Witjes; Tessel E. Galesloot; Alina Vrieling; Katja K.H. Aben; Lambertus A.L.M. Kiemeney; Egbert Oosterwijk; Mihai G. Netea; Joost L. Boormans; Antoine G. Van Der Heijden; Leo A.B. Joosten; Sita H. Vermeulen

doi:10.1136/jitc-2022-005518

Intravesical BCG in patients with non-muscle invasive bladder cancer induces trained immunity and decreases respiratory infections

Jelmer H. Van Puffelen, Boris Novakovic, Liesbeth Van Emst, Denise Kooper, Tahlita C.M. Zuiverloon, Ursula T.H. Oldenhof, J. Alfred Witjes, Tessel E. Galesloot, Alina Vrieling, Katja K.H. Aben, Lambertus A.L.M. Kiemeney, Egbert Oosterwijk, Mihai G. Netea, Joost L. Boormans, Antoine G. Van Der Heijden, Leo A.B. Joosten, Sita H. Vermeulen^*

^*Corresponding author for this work

Urology

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Background BCG is recommended as intravesical immunotherapy to reduce the risk of tumor recurrence in patients with non-muscle invasive bladder cancer (NMIBC). Currently, it is unknown whether intravesical BCG application induces trained immunity. Methods The aim of this research was to determine whether BCG immunotherapy induces trained immunity in NMIBC patients. We conducted a prospective observational cohort study in 17 NMIBC patients scheduled for BCG therapy and measured trained immunity parameters at 9 time points before and during a 1-year BCG maintenance regimen. Ex vivo cytokine production by peripheral blood mononuclear cells, epigenetic modifications, and changes in the monocyte transcriptome were measured. The frequency of respiratory infections was investigated in two larger cohorts of BCG-Treated and non-BCG treated NMIBC patients as a surrogate measurement of trained immunity. Gene-based association analysis of genetic variants in candidate trained immunity genes and their association with recurrence-free survival and progression-free survival after BCG therapy was performed to investigate the hypothesized link between trained immunity and clinical response. Results We found that intravesical BCG does induce trained immunity based on an increased production of TNF and IL-1β after heterologous ex vivo stimulation of circulating monocytes 6-12 weeks after intravesical BCG treatment; and a 37% decreased risk (OR 0.63 (95% CI 0.40 to 1.01)) for respiratory infections in BCG-Treated versus non-BCG-Treated NMIBC patients. An epigenomics approach combining chromatin immuno precipitation-sequencing and RNA-sequencing with in vitro trained immunity experiments identified enhanced inflammasome activity in BCG-Treated individuals. Finally, germline variation in genes that affect trained immunity was associated with recurrence and progression after BCG therapy in NMIBC. Conclusion We conclude that BCG immunotherapy induces trained immunity in NMIBC patients and this may account for the protective effects against respiratory infections. The data of our gene-based association analysis suggest that a link between trained immunity and oncological outcome may exist.

Original language	English
Article number	e005518
Journal	Journal for ImmunoTherapy of Cancer
Volume	11
Issue number	1
DOIs	https://doi.org/10.1136/jitc-2022-005518
Publication status	Published - 24 Jan 2023

Bibliographical note

Funding Information:
MGN was supported by an ERC Advanced Grant (#833247) and a Netherlands Organization for Scientific Research Spinoza Grant (NWO SPI 94-212). LABJ was supported by a Competitiveness Operational Programme grant of the Romanian Ministry of European Funds (P_37_762, MySMIS 103587). SHV is supported by a grant from the Netherlands Organization for Scientific Research (NWO Vidi 91717334). BN is supported by an NHMRC (Australia) Investigator Grant (APP1173314) and Project Grant (APP1157556). The BlaZIB study was financially supported by the Dutch Cancer Society (IKNL 2015-7914). The UroLife study was financially supported by Alpe d’HuZes/Dutch Cancer Society (KUN 2013-5926) and Dutch Cancer Society (2017-2/11179). Funding for the exome chip study was provided by the Netherlands Organization for Scientific Research under award number 184021007 and made available as a Rainbow Project of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL). Genetic analyses were carried out on the Dutch national e-infrastructure with the support of SURF Cooperative.

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© Author(s) (or their employer(s)) 2023.

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Intravesical BCG in patients with non-muscle invasive bladder cancer induces trained immunity and decreases respiratory infectionsFinal published version, 9.47 MBLicence: CC BY

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Van Puffelen, J. H., Novakovic, B., Van Emst, L., Kooper, D., Zuiverloon, T. C. M., Oldenhof, U. T. H., Witjes, J. A., Galesloot, T. E., Vrieling, A., Aben, K. K. H., Kiemeney, L. A. L. M., Oosterwijk, E., Netea, M. G., Boormans, J. L., Van Der Heijden, A. G., Joosten, L. A. B., & Vermeulen, S. H. (2023). Intravesical BCG in patients with non-muscle invasive bladder cancer induces trained immunity and decreases respiratory infections. Journal for ImmunoTherapy of Cancer, 11(1), Article e005518. https://doi.org/10.1136/jitc-2022-005518

@article{fe10d58aa74e47ef9f5c79a1cf9c7bfa,

title = "Intravesical BCG in patients with non-muscle invasive bladder cancer induces trained immunity and decreases respiratory infections",

abstract = "Background BCG is recommended as intravesical immunotherapy to reduce the risk of tumor recurrence in patients with non-muscle invasive bladder cancer (NMIBC). Currently, it is unknown whether intravesical BCG application induces trained immunity. Methods The aim of this research was to determine whether BCG immunotherapy induces trained immunity in NMIBC patients. We conducted a prospective observational cohort study in 17 NMIBC patients scheduled for BCG therapy and measured trained immunity parameters at 9 time points before and during a 1-year BCG maintenance regimen. Ex vivo cytokine production by peripheral blood mononuclear cells, epigenetic modifications, and changes in the monocyte transcriptome were measured. The frequency of respiratory infections was investigated in two larger cohorts of BCG-Treated and non-BCG treated NMIBC patients as a surrogate measurement of trained immunity. Gene-based association analysis of genetic variants in candidate trained immunity genes and their association with recurrence-free survival and progression-free survival after BCG therapy was performed to investigate the hypothesized link between trained immunity and clinical response. Results We found that intravesical BCG does induce trained immunity based on an increased production of TNF and IL-1β after heterologous ex vivo stimulation of circulating monocytes 6-12 weeks after intravesical BCG treatment; and a 37% decreased risk (OR 0.63 (95% CI 0.40 to 1.01)) for respiratory infections in BCG-Treated versus non-BCG-Treated NMIBC patients. An epigenomics approach combining chromatin immuno precipitation-sequencing and RNA-sequencing with in vitro trained immunity experiments identified enhanced inflammasome activity in BCG-Treated individuals. Finally, germline variation in genes that affect trained immunity was associated with recurrence and progression after BCG therapy in NMIBC. Conclusion We conclude that BCG immunotherapy induces trained immunity in NMIBC patients and this may account for the protective effects against respiratory infections. The data of our gene-based association analysis suggest that a link between trained immunity and oncological outcome may exist.",

author = "{Van Puffelen}, {Jelmer H.} and Boris Novakovic and {Van Emst}, Liesbeth and Denise Kooper and Zuiverloon, {Tahlita C.M.} and Oldenhof, {Ursula T.H.} and Witjes, {J. Alfred} and Galesloot, {Tessel E.} and Alina Vrieling and Aben, {Katja K.H.} and Kiemeney, {Lambertus A.L.M.} and Egbert Oosterwijk and Netea, {Mihai G.} and Boormans, {Joost L.} and {Van Der Heijden}, {Antoine G.} and Joosten, {Leo A.B.} and Vermeulen, {Sita H.}",

note = "Funding Information: MGN was supported by an ERC Advanced Grant (#833247) and a Netherlands Organization for Scientific Research Spinoza Grant (NWO SPI 94-212). LABJ was supported by a Competitiveness Operational Programme grant of the Romanian Ministry of European Funds (P_37_762, MySMIS 103587). SHV is supported by a grant from the Netherlands Organization for Scientific Research (NWO Vidi 91717334). BN is supported by an NHMRC (Australia) Investigator Grant (APP1173314) and Project Grant (APP1157556). The BlaZIB study was financially supported by the Dutch Cancer Society (IKNL 2015-7914). The UroLife study was financially supported by Alpe d{\textquoteright}HuZes/Dutch Cancer Society (KUN 2013-5926) and Dutch Cancer Society (2017-2/11179). Funding for the exome chip study was provided by the Netherlands Organization for Scientific Research under award number 184021007 and made available as a Rainbow Project of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL). Genetic analyses were carried out on the Dutch national e-infrastructure with the support of SURF Cooperative. Publisher Copyright: {\textcopyright} Author(s) (or their employer(s)) 2023.",

year = "2023",

month = jan,

day = "24",

doi = "10.1136/jitc-2022-005518",

language = "English",

volume = "11",

journal = "Journal for ImmunoTherapy of Cancer",

issn = "2051-1426",

publisher = "BMJ Publishing Group",

number = "1",

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Van Puffelen, JH, Novakovic, B, Van Emst, L, Kooper, D, Zuiverloon, TCM, Oldenhof, UTH, Witjes, JA, Galesloot, TE, Vrieling, A, Aben, KKH, Kiemeney, LALM, Oosterwijk, E, Netea, MG, Boormans, JL, Van Der Heijden, AG, Joosten, LAB & Vermeulen, SH 2023, 'Intravesical BCG in patients with non-muscle invasive bladder cancer induces trained immunity and decreases respiratory infections', Journal for ImmunoTherapy of Cancer, vol. 11, no. 1, e005518. https://doi.org/10.1136/jitc-2022-005518

TY - JOUR

T1 - Intravesical BCG in patients with non-muscle invasive bladder cancer induces trained immunity and decreases respiratory infections

AU - Van Puffelen, Jelmer H.

AU - Novakovic, Boris

AU - Van Emst, Liesbeth

AU - Kooper, Denise

AU - Zuiverloon, Tahlita C.M.

AU - Oldenhof, Ursula T.H.

AU - Witjes, J. Alfred

AU - Galesloot, Tessel E.

AU - Vrieling, Alina

AU - Aben, Katja K.H.

AU - Kiemeney, Lambertus A.L.M.

AU - Oosterwijk, Egbert

AU - Netea, Mihai G.

AU - Boormans, Joost L.

AU - Van Der Heijden, Antoine G.

AU - Joosten, Leo A.B.

AU - Vermeulen, Sita H.

N1 - Funding Information: MGN was supported by an ERC Advanced Grant (#833247) and a Netherlands Organization for Scientific Research Spinoza Grant (NWO SPI 94-212). LABJ was supported by a Competitiveness Operational Programme grant of the Romanian Ministry of European Funds (P_37_762, MySMIS 103587). SHV is supported by a grant from the Netherlands Organization for Scientific Research (NWO Vidi 91717334). BN is supported by an NHMRC (Australia) Investigator Grant (APP1173314) and Project Grant (APP1157556). The BlaZIB study was financially supported by the Dutch Cancer Society (IKNL 2015-7914). The UroLife study was financially supported by Alpe d’HuZes/Dutch Cancer Society (KUN 2013-5926) and Dutch Cancer Society (2017-2/11179). Funding for the exome chip study was provided by the Netherlands Organization for Scientific Research under award number 184021007 and made available as a Rainbow Project of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL). Genetic analyses were carried out on the Dutch national e-infrastructure with the support of SURF Cooperative. Publisher Copyright: © Author(s) (or their employer(s)) 2023.

PY - 2023/1/24

Y1 - 2023/1/24

N2 - Background BCG is recommended as intravesical immunotherapy to reduce the risk of tumor recurrence in patients with non-muscle invasive bladder cancer (NMIBC). Currently, it is unknown whether intravesical BCG application induces trained immunity. Methods The aim of this research was to determine whether BCG immunotherapy induces trained immunity in NMIBC patients. We conducted a prospective observational cohort study in 17 NMIBC patients scheduled for BCG therapy and measured trained immunity parameters at 9 time points before and during a 1-year BCG maintenance regimen. Ex vivo cytokine production by peripheral blood mononuclear cells, epigenetic modifications, and changes in the monocyte transcriptome were measured. The frequency of respiratory infections was investigated in two larger cohorts of BCG-Treated and non-BCG treated NMIBC patients as a surrogate measurement of trained immunity. Gene-based association analysis of genetic variants in candidate trained immunity genes and their association with recurrence-free survival and progression-free survival after BCG therapy was performed to investigate the hypothesized link between trained immunity and clinical response. Results We found that intravesical BCG does induce trained immunity based on an increased production of TNF and IL-1β after heterologous ex vivo stimulation of circulating monocytes 6-12 weeks after intravesical BCG treatment; and a 37% decreased risk (OR 0.63 (95% CI 0.40 to 1.01)) for respiratory infections in BCG-Treated versus non-BCG-Treated NMIBC patients. An epigenomics approach combining chromatin immuno precipitation-sequencing and RNA-sequencing with in vitro trained immunity experiments identified enhanced inflammasome activity in BCG-Treated individuals. Finally, germline variation in genes that affect trained immunity was associated with recurrence and progression after BCG therapy in NMIBC. Conclusion We conclude that BCG immunotherapy induces trained immunity in NMIBC patients and this may account for the protective effects against respiratory infections. The data of our gene-based association analysis suggest that a link between trained immunity and oncological outcome may exist.

AB - Background BCG is recommended as intravesical immunotherapy to reduce the risk of tumor recurrence in patients with non-muscle invasive bladder cancer (NMIBC). Currently, it is unknown whether intravesical BCG application induces trained immunity. Methods The aim of this research was to determine whether BCG immunotherapy induces trained immunity in NMIBC patients. We conducted a prospective observational cohort study in 17 NMIBC patients scheduled for BCG therapy and measured trained immunity parameters at 9 time points before and during a 1-year BCG maintenance regimen. Ex vivo cytokine production by peripheral blood mononuclear cells, epigenetic modifications, and changes in the monocyte transcriptome were measured. The frequency of respiratory infections was investigated in two larger cohorts of BCG-Treated and non-BCG treated NMIBC patients as a surrogate measurement of trained immunity. Gene-based association analysis of genetic variants in candidate trained immunity genes and their association with recurrence-free survival and progression-free survival after BCG therapy was performed to investigate the hypothesized link between trained immunity and clinical response. Results We found that intravesical BCG does induce trained immunity based on an increased production of TNF and IL-1β after heterologous ex vivo stimulation of circulating monocytes 6-12 weeks after intravesical BCG treatment; and a 37% decreased risk (OR 0.63 (95% CI 0.40 to 1.01)) for respiratory infections in BCG-Treated versus non-BCG-Treated NMIBC patients. An epigenomics approach combining chromatin immuno precipitation-sequencing and RNA-sequencing with in vitro trained immunity experiments identified enhanced inflammasome activity in BCG-Treated individuals. Finally, germline variation in genes that affect trained immunity was associated with recurrence and progression after BCG therapy in NMIBC. Conclusion We conclude that BCG immunotherapy induces trained immunity in NMIBC patients and this may account for the protective effects against respiratory infections. The data of our gene-based association analysis suggest that a link between trained immunity and oncological outcome may exist.

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U2 - 10.1136/jitc-2022-005518

DO - 10.1136/jitc-2022-005518

M3 - Article

C2 - 36693678

AN - SCOPUS:85147047887

SN - 2051-1426

VL - 11

JO - Journal for ImmunoTherapy of Cancer

JF - Journal for ImmunoTherapy of Cancer

IS - 1

M1 - e005518

ER -

Intravesical BCG in patients with non-muscle invasive bladder cancer induces trained immunity and decreases respiratory infections

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