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  • Open Access

Mcl-1 expression influcences CD8+ anti-tumor immunity.

  • 1 and
  • 1
Journal for ImmunoTherapy of Cancer20153 (Suppl 2) :P323

https://doi.org/10.1186/2051-1426-3-S2-P323

  • Published:

Keywords

  • Squamous Cell Carcinoma
  • Neck Squamous Cell Carcinoma
  • Delay Tumor Growth
  • Synergistic Response
  • Immunotherapy Strategy

The recent clinical successes of immunotherapies such as anti-PD-1 and anti-CTLA-4 antibody blockade have re-invigorated the idea that the immune system has the potential to be a powerful tool to destroy tumors. However despite ample evidence that these therapies are able to enhance the efficacy of anti-tumor CD8+ T cell responses, the association of pro-survival molecules such as Mcl-1 with this process remains poorly understood. We have previously shown that short-term in vitro co-culture of human T cells with human-derived tumor cell lines of various origins can induce the gain of senescence-like features CD8+ T cells, particularly the loss of CD27/CD28 expression and the gain of a potent suppressive function in in vitro suppression assays. In subsequent studies, we found that IL-7 could protect T cells from the development of dysfunction/suppression, and that this process is highly dependent on the expression of the pro-survival protein Mcl-1. In the current study we sought to determine whether the beneficial effects of IL-7 could also be shown in vivo in a mouse model of head and neck squamous cell carcinoma (HNSCC). We show that the use of exogenous IL-7 treatment results in a delay in tumor growth, and that the combination of IL-7 with other immunotherapies, particularly anti-PD-1 antibody blockade, results in a synergistic response which is better than either therapy alone. Further, when combined with an adoptive transfer of TCR transgenic T cells, IL-7 treatment results in enhanced delay of tumor growth and greater numbers of tumor-specific T cells in the tumor microenvironment. Similar to our previous in vitro studies, we further find that expression of Mcl-1 can have a significant effect on anti-tumor CD8+ T cells responses. Knock-down of Mcl-1 expression significantly abrogates the function of tumor-specific, adoptive-transferred T cells while the enhancement of Mcl-1 expression also enhances CD8+ function and significantly delays tumor growth. These data indicate that one benefit of existing immunotherapy strategies like IL-7 could be in the enhancement of expression of pro-survival factors like Mcl-1, and those future treatment strategies which specifically target their expression could improve anti-tumor immune responses.

Authors’ Affiliations

(1)
Cleveland Clinic, Cleveland, OH, USA

Copyright

© Pfannenstiel and Gastman 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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