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Density of tumour stroma is correlated to outcome after adoptive transfer of CD4+ and CD8+ T cells in a murine mammary carcinoma model

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Abstract

Adoptive immunotherapy shows promise for the treatment of cancer; however, partial or mixed responses remain common outcomes due to the heterogeneity of tumours. We studied three murine mammary tumour lines that express an ovalbumin-tagged version of HER-2/neu and reproducibly undergo complete regression (CR), partial regression (PR), or progressive disease (PD) after adoptive transfer of ovalbumin-specific CD8+ (OT-I) and CD4+ (OT-II) T cells. The three tumour lines were implanted in immunocompetent C57Bl/6 host mice, and established tumours were treated by adoptive transfer of naive OT-I and OT-II T cells. Tumours of the CR and PR classes triggered almost indistinguishable T cell responses in terms of activation, proliferation, trafficking to the tumour site, infiltration of tumour stroma, and intratumoural T cell proliferation; however, tumours of the PR class showed reduced infiltration of tumour epithelium by donor T cells. PD responses were associated with early impairment of T cell activation and proliferation in draining lymph node, followed by negligible infiltration of tumour tissue by donor T cells. Histopathological determinants of outcome were investigated through an unsupervised analysis of 64 untreated tumours representing the three response classes. Tumours of the CR class had proportionately more stroma, which had a looser, more collagen-rich histological appearance. Thus, the amount and composition of tumour stroma distinguished successfully (CR) from unsuccessful (PR or PD) outcomes after adoptive T cell transfer, a finding that might facilitate the design of immunotherapy trials for human breast cancer.

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Acknowledgments

We thank Wendy Lin for technical assistance with the mouse colony, and Geoff Martinson and Jeevin Shahi for assistance with genotyping. We also thank Dr. Julie Nielsen, Dr. John Webb, and Darin Wick for helpful discussions and preparation of the figures. This work was supported by the Canadian Institutes for Health Research (MOP-173868), Canadian Breast Cancer Foundation, Michael Smith Foundation for Health Research, Terry Fox New Frontiers Program (018005), and British Columbia Cancer Foundation

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Authors and Affiliations

  1. Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, 2410 Lee Avenue, Victoria, BC, V8R 6V5, Canada

    Michele L. Martin, Katy Milne, Peter H. Watson & Brad H. Nelson

  2. Department of Biology, University of Victoria, 3800 Finnerty Road, Victoria, BC, V8P 5C2, Canada

    Michele L. Martin & Brad H. Nelson

  3. Department of Biochemistry/Microbiology, University of Victoria, 3800 Finnerty Road, Victoria, BC, V8P 5C2, Canada

    Erika M. Wall, Emily Sandwith, Adam Girardin, Peter H. Watson & Brad H. Nelson

  4. Department of Pathology and Laboratory Medicine, University of British Columbia, 2329 West Mall, Vancouver, BC, V6T 1Z4, Canada

    Peter H. Watson

  5. Department of Medical Genetics, University of British Columbia, 2329 West Mall, Vancouver, BC, V6T 1Z4, Canada

    Brad H. Nelson

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  1. Michele L. Martin
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Correspondence to Brad H. Nelson.

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Martin, M.L., Wall, E.M., Sandwith, E. et al. Density of tumour stroma is correlated to outcome after adoptive transfer of CD4+ and CD8+ T cells in a murine mammary carcinoma model. Breast Cancer Res Treat 121, 753–763 (2010). https://doi.org/10.1007/s10549-009-0559-y

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