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On CD4+ T Lymphocytes in Solid Tumours
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis deals with recognition and elimination of tumours by T lymphocytes and their use in adoptive immunotherapy.

The first tumour-draining lymph node; the sentinel node, is identified by peritumoural injection of a tracer. This is the hypothesised location for the activation of tumour-reactive lymphocytes. Accordingly, proliferation and IFN-γ production in response to autologous tumour extract was detected in sentinel nodes from patients with colon and urinary bladder cancer. Reactivity in metastatic nodes was generally lower or absent, but the non-responsiveness could be subdued in long-term cultures by addition of tumour antigen and IL-2. A novel padlock-probe based method was developed for measuring the T cell receptor Vβ repertoire. Common Vβ gene expansions were detected in tumour-infiltrating lymphocytes and sentinel nodes. Thus, tumour antigens are recognised in sentinel nodes by Th1 lymphocytes, resulting in a clonally expanded cell population that can be further propagated ex vivo.

Regulatory T cells (Tregs) may contribute to tumour-induced immunosuppression. Immunohistochemical stainings against the pan-T cell marker CD3 and Treg marker FOXP3 was performed on tumour tissue from 20 historical urinary bladder cancer patients. The ratio of FOXP3+ to CD3+ cells was lower in patients alive 7 years post-cystectomy, suggesting that Tregs in bladder cancer have prognostic implications.

Lymphocytes were isolated from sentinel nodes from sixteen patients with advanced or high-risk colon cancer. In vitro expansion with addition of autologous tumour extract and IL-2 mainly promoted the outgrowth of CD4+ Th1 lymphocytes, which were safely re-transfused to the patients. Four patients responded with complete tumour regression. Survival time in the Dukes’ D patients was significantly increased compared with conventionally treated controls (2.6 versus 0.8 years; p=0.048).

In conclusion, human solid tumours are recognised in sentinel nodes and in vitro expanded sentinel node-acquired CD4+ T lymphocytes seem useful in the treatment of patients with disseminated cancer.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2007. , 68 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 295
Keyword [en]
Molecular medicine, Tumour immunology, T lymphocytes, sentinel node detection, colon cancer, urinary bladder cancer, adoptive immunotherapy
Keyword [sv]
Molekylärmedicin
Identifiers
URN: urn:nbn:se:uu:diva-8325ISBN: 978-91-554-7034-0 (print)OAI: oai:DiVA.org:uu-8325DiVA: diva2:171078
Public defence
2007-12-14, Sal X, Universitetshuset, Uppsala, 09:15
Opponent
Supervisors
Available from: 2007-11-23 Created: 2007-11-23Bibliographically approved
List of papers
1. Sentinel node lymphocytes: tumour reactive lymphocytes identified intraoperatively for the use in immunotherapy of colon cancer
Open this publication in new window or tab >>Sentinel node lymphocytes: tumour reactive lymphocytes identified intraoperatively for the use in immunotherapy of colon cancer
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2006 In: British journal of cancer, ISSN 0007-0920, Vol. 94, no 10, 1478-1484 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-96485 (URN)
Available from: 2007-11-23 Created: 2007-11-23Bibliographically approved
2. Detection of immune responses against urinary bladder cancer in sentinel lymph nodes
Open this publication in new window or tab >>Detection of immune responses against urinary bladder cancer in sentinel lymph nodes
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2006 In: European urology, ISSN 0302-2838, Vol. 49, no 1, 59-70 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-96486 (URN)
Available from: 2007-11-23 Created: 2007-11-23Bibliographically approved
3. Analysis of T-cell receptor V beta gene repertoires after immune stimulation and in malignancy by use of padlock probes and microarrays
Open this publication in new window or tab >>Analysis of T-cell receptor V beta gene repertoires after immune stimulation and in malignancy by use of padlock probes and microarrays
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2005 In: Clinical chemistry, ISSN 0009-9147, Vol. 51, no 4, 768-775 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-96487 (URN)
Available from: 2007-11-23 Created: 2007-11-23Bibliographically approved
4. Tumour infiltrating FOXP3+ regulatory T cells in urinary bladder cancer
Open this publication in new window or tab >>Tumour infiltrating FOXP3+ regulatory T cells in urinary bladder cancer
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Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-96488 (URN)
Available from: 2007-11-23 Created: 2007-11-23 Last updated: 2010-01-13Bibliographically approved
5. Sentinel node CD4+ Th1-cells induce tumour regression in humans
Open this publication in new window or tab >>Sentinel node CD4+ Th1-cells induce tumour regression in humans
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Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-96489 (URN)
Available from: 2007-11-23 Created: 2007-11-23 Last updated: 2010-01-13Bibliographically approved

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