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  • Oral presentation
  • Open Access

Virus-specific CD8+ T cells infiltrate melanoma lesions and retain function despite high PD-1 expression

  • Dan A Erkes1,
  • Toktam Mohgbeli1 and
  • Christopher M Snyder1
Journal for ImmunoTherapy of Cancer20153(Suppl 2):O6

https://doi.org/10.1186/2051-1426-3-S2-O6

Published: 4 November 2015

Keywords

MelanomaTumor Infiltrate LymphocyteVaccine VectorMelanoma LesionGp100 Antigen

It is well known that CD8+ T cell infiltration of tumors is correlated with positive patient prognosis. Because of this, many viral vaccine vectors have been created to induce expansion and infiltration of tumor-specific CD8+ T cells. Cytomegalovirus (CMV) is a herpes virus that induces a persistent/latent infection for the life of the host. It is able to drive large populations of viral-specific T cells that are fully functional and infiltrate most tissues. We have established that acute infection with a recombinant murine CMV virus expressing an altered gp100 antigen (MCMV-gp100) caused expansion and tumor infiltration of gp100-specific CD8+ T cells, leading to a therapeutic delay in the growth of B16 melanomas in mice. Coincidentally, we observed that at least 20% of the CD8+ tumor infiltrating lymphocytes (TIL) were MCMV-specific. These virus-specific T cells infiltrated tumors independently of viral replication. Unexpectedly, T cell infiltration of tumors occurred even in latently infected animals, long after viral replication had been controlled. Together, these data suggest that virus-specific CD8+ T cells can become TIL, even long after the primary infection. We were curious about differences between tumor and virus-specific CD8+ TIL. As expected, after acute MCMV-gp100 infection, gp100-specific CD8+ TIL were PD-1hi and markedly dysfunctional. Virus-specific CD8+ T cells were also PD-1hi in the tumor after acute MCMV-gp100 infection, but these cells remained fully functional. PD-1 is an activation marker expressed on recently stimulated CD8+ T cells and both gp100-specific and virus-specific T cells expressed PD-1 after acute MCMV-gp100 infection. In the circulation of tumor-bearing mice or in the absence of a tumor, both gp100-specific and virus-specific CD8+ T cells lost PD-1 expression over time. However, PD-1hi cells that migrated into tumors retained expression of PD-1 regardless of specificity. Strikingly, introducing B16 tumors into MCMV-gp100 latently infected mice after PD-1 expression was lost, resulted in PD-1 up-regulation on and subsequent dysfunction of gp100-specific T cells that entered the tumor, but not virus-specific T cells found in the same tumors. Together, these data suggest that the tumor environment sustains PD-1 expression on recently activated CD8+ TIL independently of antigen in the tumor, but that the presence of antigen in the tumor drives subsequent CD8+ TIL dysfunction.

Authors’ Affiliations

(1)
Thomas Jefferson University, Philadelphia, USA

Copyright

© Erkes et al. 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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