Redirecting migration of T cells to chemokine secreted from tumors by genetic modification with CXCR2

Michael H. Kershaw, Gang Wang, Jennifer A. Westwood, Russell K. Pachynski, H. Lee Tiffany, Francesco M. Marincola, Ena Wang, Howard A. Young, Philip M. Murphy, Patrick Hwu

Research output: Contribution to journalArticle

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Abstract

T-cell-based immunotherapies provide a promising means of cancer treatment although durable antitumor responses are infrequent. A potential reason for these shortcomings may lie in the observed lack of trafficking of specific T cells to tumor. Our increasing knowledge of the process of trafficking involving adhesion molecules and chemokines affords us the opportunity to intervene and correct deficiencies in this process. Chemokines can be expressed by a range of tumors and may serve as suitable targets for directing specific T cells toward tumor. We initially sought to identify which chemokines were produced by a range of human tumor cell lines, and which chemokines and chemokine receptors were expressed by cultured T cells. We identified two chemokines: Growth-Regulated Oncogene-α (Gro-α; CXCL1) and Regulated on Activation Normal T Cell-Expressed and Secreted (RANTES; CCL5), to be secreted by several human tumor cell lines. Expression was also detected in fine-needle aspirates of melanoma from patients. In addition, we determined the expression of several chemokine receptors on cultured human T cells including CCR1, CCR2, CCR4, CCR5, CXCR3, and CXCR4. Cultured, activated human T cells expressed the chemokines lymphotactin (XCL1), RANTES, macrophage inflammatory protein-1α (MIP-1α; CCL3) and MIP-1β (CCL4), but no appreciable Gro-α. In a strategy to direct T cells toward chemokines expressed by tumors we chose Gro-α as the target chemokine because it was produced by tumor and not by T cells themselves. However, T cells did not express the receptor for Gro-α, CXCR2, and therefore, T cells were transduced with a retroviral vector encoding CXCR2. Calcium ion mobilization, an important first step in chemokine receptor signaling, was subsequently demonstrated in transduced T cells in response to Gro-α. In addition, Gro-α was chemotactic for T cells expressing CXCR2 in vitro toward both recombinant protein and tumor-derived chemokine. Interestingly we demonstrate, for the first time, that Gro-α was able to induce interferon-γ (IFN-γ) secretion from transduced T cells, thereby extending our knowledge of other potential functions of CXCR2. This study demonstrates the feasibility of redirecting the migration properties of T cells toward chemokines secreted by tumors.

Original languageEnglish
Pages (from-to)1971-1980
Number of pages10
JournalHuman Gene Therapy
Volume13
Issue number16
DOIs
Publication statusPublished - 2002
Externally publishedYes

Fingerprint

Chemokines
T-Lymphocytes
Neoplasms
Chemokine Receptors
Chemokine CCL5
Tumor Cell Line
Interleukin-8B Receptors
Macrophage Inflammatory Proteins
Feasibility Studies
Oncogenes
Recombinant Proteins
Immunotherapy
Interferons
Needles
Cultured Cells
Melanoma

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Kershaw, M. H., Wang, G., Westwood, J. A., Pachynski, R. K., Tiffany, H. L., Marincola, F. M., ... Hwu, P. (2002). Redirecting migration of T cells to chemokine secreted from tumors by genetic modification with CXCR2. Human Gene Therapy, 13(16), 1971-1980. https://doi.org/10.1089/10430340260355374

Redirecting migration of T cells to chemokine secreted from tumors by genetic modification with CXCR2. / Kershaw, Michael H.; Wang, Gang; Westwood, Jennifer A.; Pachynski, Russell K.; Tiffany, H. Lee; Marincola, Francesco M.; Wang, Ena; Young, Howard A.; Murphy, Philip M.; Hwu, Patrick.

In: Human Gene Therapy, Vol. 13, No. 16, 2002, p. 1971-1980.

Research output: Contribution to journalArticle

Kershaw, MH, Wang, G, Westwood, JA, Pachynski, RK, Tiffany, HL, Marincola, FM, Wang, E, Young, HA, Murphy, PM & Hwu, P 2002, 'Redirecting migration of T cells to chemokine secreted from tumors by genetic modification with CXCR2', Human Gene Therapy, vol. 13, no. 16, pp. 1971-1980. https://doi.org/10.1089/10430340260355374
Kershaw, Michael H. ; Wang, Gang ; Westwood, Jennifer A. ; Pachynski, Russell K. ; Tiffany, H. Lee ; Marincola, Francesco M. ; Wang, Ena ; Young, Howard A. ; Murphy, Philip M. ; Hwu, Patrick. / Redirecting migration of T cells to chemokine secreted from tumors by genetic modification with CXCR2. In: Human Gene Therapy. 2002 ; Vol. 13, No. 16. pp. 1971-1980.
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