Targeting immune checkpoint pathways overcomes tumor-induced CD8+ T cell suppression
© Pfannenstiel and Gastman; licensee BioMed Central Ltd. 2014
Published: 6 November 2014
The immune system has the potential to be a powerful tool to destroy tumors. However despite ample evidence of anti-tumor immune responses in many patients, as well as years of immunotherapy development, truly effective immune-based therapies remain out of reach. 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 in both CD4+ and CD8+ T cells, particularly the loss of CD27/CD28 expression. We found this tumor-induced senescence does not involve activation/proliferation, and also results in 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 CD27/CD28 loss and acquisition of suppressive function and that this process is highly dependent on the expression of the anti-apoptotic protein Mcl-1.
In the current study we sought to determine whether a similar process could not only be found in mice, but also in tumor-resident T cells (TIL) collected from human patient specimens. We show that the process of tumor-induced dysfunction also induces the expression of PD-1 in both human and mouse T cells in vitro, and that tumor-exposed mouse T cells are also capable of suppressive function. Similar to published reports, we find tumor-resident human CD8+ TIL to have significant losses in CD27/CD28 expression, and that loss of these markers is accompanied by the gain in PD-1 expression, as well as other known checkpoint inhibitors, especially Tim-3. In mice, TIL also highly express PD-1, Tim-3, and Lag-3 but similar to in vitro studies, do not lose expression of CD27 and CD28. Using cell sorting to isolate CD3+ CD8+ PD-1+ Tim-3+ T cells from both mouse and human tumors, we find that this population is able to suppress autologous or syngeneic responder T cells in ex vivo proliferation assays. We further show that use of antibody blockade of PD-1 and Tim-3 signaling in vitro and in vivo prevents the development of suppression. Ongoing studies will examine the signaling mechanisms responsible, especially by evaluating the role of Mcl-1 expression in generation of dysfunctional CD8 T cells in vivo. These studies demonstrate that tumor-derived factors can induce suppressive CD8+ T cells, and that blockade of negative regulators of T cell function can help prevent this process, indicating an additional benefit to the clinical use of these immunotherapies.
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.