Adaptive immunity in urothelial cancer : molecular and clinical aspects
Author: Krantz, David
Date: 2018-10-26
Location: Rehabsalen, S2:01, Karolinska University Hospital, Solna
Time: 09.00
Department: Inst för medicin, Solna / Dept of Medicine, Solna
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Thesis (2.742Mb)
Abstract
In the battle between the immune system and cancer, tolerance mechanisms otherwise protective against autoimmunity, are exploited to halt the anti-tumor immune response. In this model, tumors turn distinct parts of the immune system against each other; suppressive cells such as regulatory T cells (Tregs) are hijacked to obstruct effector lymphocytes in their attempt to eradicate the tumor. We explored the effects of this immunomodulation on Tregs, effector T cells (Teff) and B cells in patients with urinary bladder cancer (UBC) and examined what impact chemotherapy has on this process.
Puzzled by our previous finding of tumor-infiltrating Tregs to correlate to a favorable prognosis in patients with UBC, we sought to corroborate our results and ensure that we had not mistaken Teff cells for Treg cells. This was not the case, since we demonstrated tumor-infiltrating CD4+FOXP3+ T cells to be phenotypically, functionally and epigenetically stably committed Tregs. In search for a mechanistic explanation to the apparent favorable role of Tregs in UBC, we found this cell population to mediate suppression of the prometastatic factor MMP2, produced by M2 macrophages and UBC cells at the invasive front of the tumor microenvironment (TME). This finding supports the model where Tregs, by controlling inflammation, may benefit patients with inflammation-driven cancers.
In our initial investigation of chemotherapeutic effects on lymphocytes, we found Doxorubicin to enhance the antigen presenting ability of B cells, with a subsequent increased activation of CD4+ T cells. This effect was mediated by an increased expression of the co-stimulatory molecule CD86, together with an altered cytokine profile including IL-10 and TNFα. The findings were translatable to the clinical setting, since CD86 expression was increased on circulating B cells of patients treated with Doxorubicin-containing neoadjuvant chemotherapy (NAC). When further evaluating the effects of chemotherapy on the T cell compartment, we changed scenery from peripheral blood to the Sentinel node (SN). CD8+ Teff exhaustion was demonstrated to be reduced after NAC treatment, while cytotoxicity was increased. In complete responders (CRs) to NAC, these cells were functionally and epigenetically committed effectors. For CD4+ Teff cells, tumor-specific reactivity was observed after NAC. In contrast, Tregs were attenuated by NAC in a dose-dependent manner with decreased frequency and reduced effector molecule expression. Also, CRs had higher Teff to activated Treg ratio, promoting antitumoral T cell activation. In our further examination of SN T cells we wondered if their proteome was altered by the tumor. We found growth- and immune signaling to be up-regulated in SN Tregs. Most significantly, Interleukin (IL)-16 was identified as central in SN Treg signaling, Furthermore, direct contact with tumoral factors increased Treg IL-16 processing into its bioactive forms and this effect was mediated by active caspase-3.
In conclusion, the adaptive arm of the immune system in the TME is heavily modulated in patients with UBC, where NAC contributes with substantial positive effects on this system. The observed suppression of tumor promoting inflammation by Tregs, manifested by inhibition of M2 macrophage functions, suggests the view of Tregs as a clear-cut negative force in tumor immunity to be a reductionistic and unfortunate vision.
Puzzled by our previous finding of tumor-infiltrating Tregs to correlate to a favorable prognosis in patients with UBC, we sought to corroborate our results and ensure that we had not mistaken Teff cells for Treg cells. This was not the case, since we demonstrated tumor-infiltrating CD4+FOXP3+ T cells to be phenotypically, functionally and epigenetically stably committed Tregs. In search for a mechanistic explanation to the apparent favorable role of Tregs in UBC, we found this cell population to mediate suppression of the prometastatic factor MMP2, produced by M2 macrophages and UBC cells at the invasive front of the tumor microenvironment (TME). This finding supports the model where Tregs, by controlling inflammation, may benefit patients with inflammation-driven cancers.
In our initial investigation of chemotherapeutic effects on lymphocytes, we found Doxorubicin to enhance the antigen presenting ability of B cells, with a subsequent increased activation of CD4+ T cells. This effect was mediated by an increased expression of the co-stimulatory molecule CD86, together with an altered cytokine profile including IL-10 and TNFα. The findings were translatable to the clinical setting, since CD86 expression was increased on circulating B cells of patients treated with Doxorubicin-containing neoadjuvant chemotherapy (NAC). When further evaluating the effects of chemotherapy on the T cell compartment, we changed scenery from peripheral blood to the Sentinel node (SN). CD8+ Teff exhaustion was demonstrated to be reduced after NAC treatment, while cytotoxicity was increased. In complete responders (CRs) to NAC, these cells were functionally and epigenetically committed effectors. For CD4+ Teff cells, tumor-specific reactivity was observed after NAC. In contrast, Tregs were attenuated by NAC in a dose-dependent manner with decreased frequency and reduced effector molecule expression. Also, CRs had higher Teff to activated Treg ratio, promoting antitumoral T cell activation. In our further examination of SN T cells we wondered if their proteome was altered by the tumor. We found growth- and immune signaling to be up-regulated in SN Tregs. Most significantly, Interleukin (IL)-16 was identified as central in SN Treg signaling, Furthermore, direct contact with tumoral factors increased Treg IL-16 processing into its bioactive forms and this effect was mediated by active caspase-3.
In conclusion, the adaptive arm of the immune system in the TME is heavily modulated in patients with UBC, where NAC contributes with substantial positive effects on this system. The observed suppression of tumor promoting inflammation by Tregs, manifested by inhibition of M2 macrophage functions, suggests the view of Tregs as a clear-cut negative force in tumor immunity to be a reductionistic and unfortunate vision.
List of papers:
I. Winerdal ME, Krantz D, Hartana CA, Zirakzadeh AA, Linton L, Bergman EA, Rosenblatt R, Vasko J, Alamdari F, Hansson J, Holmström B, Johansson M, Winerdal M, Marits P, Sherif A, and Winqvist O. Urinary bladder cancer Tregs suppress MMP2 and potentially regulate invasiveness. Cancer Immunology Research. 2018 May 6(5):528-538.
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II. Zirakzadeh AA, Kinn J, Krantz D, Rosenblatt R, Winerdal ME, Hu J, Hartana CA, Lundgren C, Bergman EA, Johansson M, Holmström B, Hansson J, Sidikii A, Vasko J, Marits P, Sherif A, Winqvist O. Doxorubicin enhances the capacity of B cells to activate T cells in urothelial urinary bladder cancer. Clinical Immunology. 2017 Mar 176:63-70.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Krantz D, Hartana CA, Winerdal ME, Johansson M, Alamdari F, Jakubczyk T, Huge Y, Aljabery F, Palmqvist K, Zirakzadeh AA, Holmström B, Riklund K, Sherif A, Winqvist O. Neoadjuvant chemotherapy reinforces the anti-tumor T cell response in urothelial urinary bladder cancer. European Urology. 2018 Jul 16. pii: S0302-2838(18)30476-7.
Fulltext (DOI)
Pubmed
IV. Krantz D, Mints M, Winerdal ME, Riklund K, Rutishauser D, Zubarev R, Zirakzadeh AA, Alamdari F, Hansson J, Holmström B, Johansson M, Sherif A, Winqvist O. IL-16 processing in sentinel node Tregs is a factor in tumor immunity. [Manuscript]
I. Winerdal ME, Krantz D, Hartana CA, Zirakzadeh AA, Linton L, Bergman EA, Rosenblatt R, Vasko J, Alamdari F, Hansson J, Holmström B, Johansson M, Winerdal M, Marits P, Sherif A, and Winqvist O. Urinary bladder cancer Tregs suppress MMP2 and potentially regulate invasiveness. Cancer Immunology Research. 2018 May 6(5):528-538.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Zirakzadeh AA, Kinn J, Krantz D, Rosenblatt R, Winerdal ME, Hu J, Hartana CA, Lundgren C, Bergman EA, Johansson M, Holmström B, Hansson J, Sidikii A, Vasko J, Marits P, Sherif A, Winqvist O. Doxorubicin enhances the capacity of B cells to activate T cells in urothelial urinary bladder cancer. Clinical Immunology. 2017 Mar 176:63-70.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Krantz D, Hartana CA, Winerdal ME, Johansson M, Alamdari F, Jakubczyk T, Huge Y, Aljabery F, Palmqvist K, Zirakzadeh AA, Holmström B, Riklund K, Sherif A, Winqvist O. Neoadjuvant chemotherapy reinforces the anti-tumor T cell response in urothelial urinary bladder cancer. European Urology. 2018 Jul 16. pii: S0302-2838(18)30476-7.
Fulltext (DOI)
Pubmed
IV. Krantz D, Mints M, Winerdal ME, Riklund K, Rutishauser D, Zubarev R, Zirakzadeh AA, Alamdari F, Hansson J, Holmström B, Johansson M, Sherif A, Winqvist O. IL-16 processing in sentinel node Tregs is a factor in tumor immunity. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Marits, Per
Co-supervisor: Winqvist, Ola
Issue date: 2018-10-05
Rights:
Publication year: 2018
ISBN: 978-91-7831-225-2
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