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On CD4+ T Lymphocytes in Solid Tumours
Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
2007 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis , 2007. , s. 68
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 295
Nyckelord [en]
Molecular medicine, Tumour immunology, T lymphocytes, sentinel node detection, colon cancer, urinary bladder cancer, adoptive immunotherapy
Nyckelord [sv]
Molekylärmedicin
Identifikatorer
URN: urn:nbn:se:uu:diva-8325ISBN: 978-91-554-7034-0 (tryckt)OAI: oai:DiVA.org:uu-8325DiVA, id: diva2:171078
Disputation
2007-12-14, Sal X, Universitetshuset, Uppsala, 09:15
Opponent
Handledare
Tillgänglig från: 2007-11-23 Skapad: 2007-11-23Bibliografiskt granskad
Delarbeten
1. Sentinel node lymphocytes: tumour reactive lymphocytes identified intraoperatively for the use in immunotherapy of colon cancer
Öppna denna publikation i ny flik eller fönster >>Sentinel node lymphocytes: tumour reactive lymphocytes identified intraoperatively for the use in immunotherapy of colon cancer
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2006 Ingår i: British journal of cancer, ISSN 0007-0920, Vol. 94, nr 10, s. 1478-1484Artikel i tidskrift (Refereegranskat) Published
Identifikatorer
urn:nbn:se:uu:diva-96485 (URN)
Tillgänglig från: 2007-11-23 Skapad: 2007-11-23Bibliografiskt granskad
2. Detection of immune responses against urinary bladder cancer in sentinel lymph nodes
Öppna denna publikation i ny flik eller fönster >>Detection of immune responses against urinary bladder cancer in sentinel lymph nodes
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2006 Ingår i: European urology, ISSN 0302-2838, Vol. 49, nr 1, s. 59-70Artikel i tidskrift (Refereegranskat) Published
Identifikatorer
urn:nbn:se:uu:diva-96486 (URN)
Tillgänglig från: 2007-11-23 Skapad: 2007-11-23Bibliografiskt granskad
3. Analysis of T-cell receptor V beta gene repertoires after immune stimulation and in malignancy by use of padlock probes and microarrays
Öppna denna publikation i ny flik eller fönster >>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 Ingår i: Clinical chemistry, ISSN 0009-9147, Vol. 51, nr 4, s. 768-775Artikel i tidskrift (Refereegranskat) Published
Identifikatorer
urn:nbn:se:uu:diva-96487 (URN)
Tillgänglig från: 2007-11-23 Skapad: 2007-11-23Bibliografiskt granskad
4. Tumour infiltrating FOXP3+ regulatory T cells in urinary bladder cancer
Öppna denna publikation i ny flik eller fönster >>Tumour infiltrating FOXP3+ regulatory T cells in urinary bladder cancer
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Manuskript (Övrigt vetenskapligt)
Identifikatorer
urn:nbn:se:uu:diva-96488 (URN)
Tillgänglig från: 2007-11-23 Skapad: 2007-11-23 Senast uppdaterad: 2010-01-13Bibliografiskt granskad
5. Sentinel node CD4+ Th1-cells induce tumour regression in humans
Öppna denna publikation i ny flik eller fönster >>Sentinel node CD4+ Th1-cells induce tumour regression in humans
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Manuskript (Övrigt vetenskapligt)
Identifikatorer
urn:nbn:se:uu:diva-96489 (URN)
Tillgänglig från: 2007-11-23 Skapad: 2007-11-23 Senast uppdaterad: 2010-01-13Bibliografiskt granskad

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