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Colon carcinoma cells induce CXCL11-dependent migration of CXCR3-expressing cytotoxic T lymphocytes in organotypic culture

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Abstract

Adoptive immunotherapy of cancer patients with cytolytic T lymphocytes (CTL) has been hampered by the inability of the CTL to home into tumors in vivo. Chemokines can attract T lymphocytes to the tumor site, as demonstrated in animal models, but the role of chemokines in T-lymphocyte trafficking toward human tumor cells is relatively unexplored. In the present study, the role of chemokines and their receptors in the migration of a colon carcinoma (CC) patient’s CTL toward autologous tumor cells has been studied in a novel three-dimensional organotypic CC culture. CTL migration was mediated by chemokine receptor CXCR3 expressed by the CTL and CXCL11 chemokine secreted by the tumor cells. Excess CXCL11 or antibodies to CXCL11 or CXCR3 inhibited migration of CTL to tumor cells. T cell and tumor cell analyses for CXCR3 and CXCL11 expression, respectively, in ten additional CC samples, may suggest their involvement in other CC patients. Our studies, together with previous studies indicating angiostatic activity of CXCL11, suggest that CXCL11 may be useful as an immunotherapeutic agent for cancer patients when transduced into tumor cells or fused to tumor antigen-specific Ab.

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Abbreviations

Ab:

Antibody

Ag:

Antigen

CC:

Colon carcinoma

CTL:

Cytotoxic T lymphocyte

DC:

Dendritic cell

EBV:

Epstein–Barr virus

E:T:

Effector-to-target ratio

FCFB/1:

Fetal colon fibroblast

GM-CSF:

Granulocyte–macrophage colony-stimulating factor

IFN:

Interferon

IL:

Interleukin

LAK:

Lymphokine-activated killer

mAb:

Monoclonal antibody

MLTC:

Mixed lymphocyte tumor cell culture

PBMC:

Peripheral blood mononuclear cells

PCR:

Polymerase chain reaction

TIL:

Tumor infiltrating lymphocytes

TNF:

Tumor necrosis factor

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Acknowledgments

We thank James Hayden for his advice in microscopy imaging and Jeffrey S. Faust for assistance in flow cytometry analyses. We also thank Elsa Aglow for providing assistance in histotechnology. This work is supported by National Institute of Health grants CA74294, and CA10815, by a grant from Corixa Corporation, by Intramural National Cancer Institute Funds, and by the Commonwealth Universal Research Enhancement program, Pennsylvania Department of Health.

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Authors and Affiliations

  1. The Wistar Institute, 3601 Spruce Street, Philadelphia, PA, 19104, USA

    Klara Berencsi, Pyapalli Rani, Rajasekharan Somasundaram, Tianqian Zhang, Jiri Kalabis, Laura Caputo, Rolf Swoboda & Dorothee Herlyn

  2. Division of Medical Science, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA

    Neal J. Meropol, John P. Hoffman, Elin Sigurdson & Lydia Giles

  3. Division of Population Science, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA

    Neal J. Meropol

  4. Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, 19104, USA

    Emma Furth

  5. Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, 20892, USA

    Francesco Marincola

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  1. Klara Berencsi
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  2. Neal J. Meropol
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  7. Rajasekharan Somasundaram
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  14. Dorothee Herlyn
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Correspondence to Dorothee Herlyn.

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Berencsi, K., Meropol, N.J., Hoffman, J.P. et al. Colon carcinoma cells induce CXCL11-dependent migration of CXCR3-expressing cytotoxic T lymphocytes in organotypic culture. Cancer Immunol Immunother 56, 359–370 (2007). https://doi.org/10.1007/s00262-006-0190-2

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  • DOI: https://doi.org/10.1007/s00262-006-0190-2

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