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Volume 3 Supplement 2

30th Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2015)

  • Poster presentation
  • Open Access

PD-1 blockade upregulate TIM-3 expression as a compensatory regulation of immune check point receptors in HNSCC TIL

  • 1 and
  • 2
Journal for ImmunoTherapy of Cancer20153(Suppl 2):P196

https://doi.org/10.1186/2051-1426-3-S2-P196

Published: 4 November 2015

Keywords

  • Tumor Infiltrate Lymphocyte
  • Compensatory Regulation
  • Persistent Tumor
  • Check Point Receptor
  • Suppressive Status
Programmed Death 1 (PD-1) and T cell Ig and mucin domain-3 protein (Tim-3) are immune check point receptors that are upregulated on tumor infiltrating lymphocytes (TIL) in tumor-bearing mice and humans. As anti-PD-1 single agent response rates are still relatively low (20%) in HNC patients, it is important to learn how different inhibitory check point receptors work together to maintain the suppressive status of immune system. We observed that PD-1 and Tim-3 co-expression is associated with an exhausted phenotype of HNSCC TIL of patients, demonstrating the highest PD-1 levels in Tim-3 double positive TIL. We also observed that PD-1+/Tim-3+ TIL manifest dampened in Akt/p-S6 activation upon TCR stimulation, leading us to infer the potential for signaling cross-talk between PD-1 and Tim-3 downstream signaling pathways. Indeed, in freshly isolated HNSCC TIL, PD-1-/TIM-3+ T cells showed higher baseline expression of p-SHP-2 (p < 0.01) which is triggered upon PD-1 ligation. In addition, PD-1 blockade using nivolumab of human HNSCC TIL led to upregulation of Tim-3 expression, suggesting a circuit of compensatory, cross-talk signaling and permitting escape from anti-PD-1 blockade during TCR stimulation. In a murine HNC tumor model, anti-PD-1 treatment modestly suppressed tumor growth, but in TIL from persistent tumors in these mice, Tim-3 expression was dramatically upregulated after PD-1 blockade. Taken together, in response to PD-1 blockade, the most exhausted TIL appear to upregulate Tim-3 as a compensatory mechanism, supporting dual targeting, which may provide new therapeutic strategy for cancer immunotherapy.
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Authors’ Affiliations

(1)
University of Pittsburgh Hillman Cancer Center, Pittsburgh, USA
(2)
University of Pittsburgh Cancer Institute, Pittsburgh, USA

Copyright

© Shayan and Ferris 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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