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Functional endogenous cytotoxic T lymphocytes are generated to multiple antigens co-expressed by progressing tumors; after intra-tumoral IL-2 therapy these effector cells eradicate established tumors

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Abstract

Tumors contain many antigens that may be recognized by the immune system. It is not known whether these antigens, and the epitopes within these antigens, can all be recognized by the anti-tumor immune response or if such responses are restricted to a few dominant epitopes. Effector function of endogenous cytotoxic T lymphocytes (CTL) generated during tumor progression has previously been assessed by indirect, ex vivo assays, which often focused on a single antigen. Therefore, we evaluated the endogenous in vivo CTL response to multiple neo tumor antigens using murine Lewis lung carcinoma tumor cells transfected with ovalbumin or a polyepitope construct. Both express multiple MHC class I-restricted epitopes. Ovalbumin contains a known hierarchy of epitopes for given MHC molecules, whilst the polyepitope expresses a number of dominant epitopes. We show that as tumors progress, potent effector CTL are generated in vivo that are restricted to dominant epitopes; we did not see the responses to subdominant or cryptic epitopes. Our data show that the CTL recognizing tumor antigens vary in their lytic capacity, as the CTL responding to two of the four epitopes were particularly potent killers. The presence of these effector CTLs did not prevent tumor growth. However, intra-tumoral IL-2 treatment altered the potency, but not the hierarchy, of these CTL such that they mediated tumor regression. These results have implications for immunotherapy protocols.

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Abbreviations

CM:

Complete media

DLN:

Draining lymph node

LL:

Lewis lung carcinoma

LN:

Lymph node

TIL:

Tumor-infiltrating lymphocyte

sOVA:

Secretory ovalbumin

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Acknowledgements

This work was supported by the National Health and Medical Research Council of Australia (NH&MRC), the State Government Insurance Commission (SGIC) and the RAINE Medical Research Foundation.

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Authors and Affiliations

  1. School of Medicine and Pharmacology, University of Western Australia, 4th Floor, G Block, Queen Elizabeth II Medical Centre, Perth, WA, 6009, Australia

    Christine S. Bundell, Connie Jackaman, Bruce W. S. Robinson & Delia J. Nelson

  2. Western Australian Biomedical Research Institute, Kent St., Curtin University, Bentley, WA, 6102, Australia

    Delia J. Nelson

  3. West Australian Institute for Medical Research, Queen Elizabeth II Medical Centre, Perth, WA, 6009, Australia

    Bruce W. S. Robinson

  4. Queensland Institute of Medical Research, Post Office Royal Brisbane Hospital, Brisbane, QLD, 4029, Australia

    Andreas Suhrbier

  5. School of Biomedical Sciences, Kent St., Curtin University, Bentley, WA, 6102, Australia

    Delia J. Nelson

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  1. Christine S. Bundell
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Correspondence to Delia J. Nelson.

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Bundell, C.S., Jackaman, C., Suhrbier, A. et al. Functional endogenous cytotoxic T lymphocytes are generated to multiple antigens co-expressed by progressing tumors; after intra-tumoral IL-2 therapy these effector cells eradicate established tumors. Cancer Immunol Immunother 55, 933–947 (2006). https://doi.org/10.1007/s00262-005-0086-6

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  • DOI: https://doi.org/10.1007/s00262-005-0086-6

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