Intravesical BCG in patients with non-muscle invasive bladder cancer induces trained immunity and decreases respiratory infections
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 whe...
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BMJ Publishing Group
2023-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/1/e005518.full |
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| author | J Alfred Witjes Alina Vrieling Mihai G Netea Leo A B Joosten Katja K H Aben Sita H Vermeulen Joost L Boormans Antoine G van der Heijden Boris Novakovic Jelmer H van Puffelen Liesbeth van Emst Denise Kooper Tahlita C M Zuiverloon Ursula T H Oldenhof Tessel E Galesloot Lambertus A L M Kiemeney Egbert Oosterwijk |
| author_facet | J Alfred Witjes Alina Vrieling Mihai G Netea Leo A B Joosten Katja K H Aben Sita H Vermeulen Joost L Boormans Antoine G van der Heijden Boris Novakovic Jelmer H van Puffelen Liesbeth van Emst Denise Kooper Tahlita C M Zuiverloon Ursula T H Oldenhof Tessel E Galesloot Lambertus A L M Kiemeney Egbert Oosterwijk |
| author_sort | J Alfred Witjes |
| collection | DOAJ |
| description | 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. Future studies should further investigate how trained immunity affects the antitumor immune responses in BCG-treated NMIBC patients |
| format | Article |
| id | doaj-art-f160d417e5fc4088a9372dbbdff54fa8 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2023-01-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-f160d417e5fc4088a9372dbbdff54fa82025-01-29T10:15:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-01-0111110.1136/jitc-2022-005518Intravesical BCG in patients with non-muscle invasive bladder cancer induces trained immunity and decreases respiratory infectionsJ Alfred Witjes0Alina Vrieling1Mihai G Netea2Leo A B Joosten3Katja K H Aben4Sita H Vermeulen5Joost L Boormans6Antoine G van der Heijden7Boris Novakovic8Jelmer H van Puffelen9Liesbeth van Emst10Denise Kooper11Tahlita C M Zuiverloon12Ursula T H Oldenhof13Tessel E Galesloot14Lambertus A L M Kiemeney15Egbert Oosterwijk16Department of Urology, Radboudumc, Nijmegen, The NetherlandsDepartment for Health Evidence, Radboud Univerity Medical Center, Nijmegen, The NetherlandsInternal Medicine, Radboud University Medical Center, Nijmegen, The NetherlandsDepartment of Internal Medicine, Radboudumc, Nijmegen, The NetherlandsDepartment for Health Evidence, Radboudumc, Nijmegen, The NetherlandsDepartment for Health Evidence, Radboudumc, Nijmegen, The NetherlandsDepartment of Urology, Erasmus MC Cancer Centre, Rotterdam, The NetherlandsDepartment of Urology, Radboud University Medical Center, Nijmegen, The NetherlandsDepartment of Paediatrics, Murdoch Children`s Research Institute, Melbourne, Victoria, AustraliaDepartment of Internal Medicine, Radboudumc, Nijmegen, The NetherlandsDepartment of Internal Medicine, Radboudumc, Nijmegen, The NetherlandsDepartment of Urology, Erasmus MC Cancer Centre, Rotterdam, The NetherlandsDepartment of Urology, Erasmus MC Cancer Centre, Rotterdam, The NetherlandsDepartment for Health Evidence, Radboudumc, Nijmegen, The NetherlandsDepartment for Health Evidence, Radboudumc, Nijmegen, The NetherlandsDepartment for Health Evidence, Radboudumc, Nijmegen, The NetherlandsDepartment of Urology, Radboudumc, Nijmegen, The NetherlandsBackground 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. Future studies should further investigate how trained immunity affects the antitumor immune responses in BCG-treated NMIBC patientshttps://jitc.bmj.com/content/11/1/e005518.full |
| spellingShingle | J Alfred Witjes Alina Vrieling Mihai G Netea Leo A B Joosten Katja K H Aben Sita H Vermeulen Joost L Boormans Antoine G van der Heijden Boris Novakovic Jelmer H van Puffelen Liesbeth van Emst Denise Kooper Tahlita C M Zuiverloon Ursula T H Oldenhof Tessel E Galesloot Lambertus A L M Kiemeney Egbert Oosterwijk Intravesical BCG in patients with non-muscle invasive bladder cancer induces trained immunity and decreases respiratory infections Journal for ImmunoTherapy of Cancer |
| title | Intravesical BCG in patients with non-muscle invasive bladder cancer induces trained immunity and decreases respiratory infections |
| title_full | Intravesical BCG in patients with non-muscle invasive bladder cancer induces trained immunity and decreases respiratory infections |
| title_fullStr | Intravesical BCG in patients with non-muscle invasive bladder cancer induces trained immunity and decreases respiratory infections |
| title_full_unstemmed | Intravesical BCG in patients with non-muscle invasive bladder cancer induces trained immunity and decreases respiratory infections |
| title_short | Intravesical BCG in patients with non-muscle invasive bladder cancer induces trained immunity and decreases respiratory infections |
| title_sort | intravesical bcg in patients with non muscle invasive bladder cancer induces trained immunity and decreases respiratory infections |
| url | https://jitc.bmj.com/content/11/1/e005518.full |
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