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  • Open Access

Level of PD-1 expression on CD8+ T cells influence prognosis and respond to PD-1 therapy in a murine model

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Journal for ImmunoTherapy of Cancer20153 (Suppl 2) :P228

https://doi.org/10.1186/2051-1426-3-S2-P228

  • Published:

Keywords

  • Squamous Cell Carcinoma
  • Good Clinical Outcome
  • Neck Squamous Cell Carcinoma
  • Tumor Infiltrate Lymphocyte
  • Optimal Tumor

Introduction

Prognosis varies dramatically in head and neck squamous cell carcinoma (HNSCC) based on HPV status. In HPV+ patients, programmed death (PD)-1 expression has been linked to a better clinical outcome. We hypothesized that extent of PD-1 expression may differentially impact T cell phenotype, patient prognosis and response to anti-PD-1 immunotherapy in a murine HPV+ cancer model.

Material and methods

Freshly isolated tumor infiltrating lymphocytes (TIL) from HNSCC patients were stained by flow cytometry for expression level of PD-1 expression (PD-1high vs. PD-1low), granzyme B, or IFN-y secretion by ELISPOT. The prognostic impact of PD-1high vs. PD-1low T cells was determined in a cohort of HNSCC patients (n=56, median follow up=19 mo). In a murine HNSCC model, PD-1high and PD-1low fractions were compared from CD3+ CD8+ PD-1+ cells and analyzed according to different treatment groups (untreated, anti-PD-1 mAb, radiotherapy and 3 different anti-PD-1/radiotherapy combinations).

Results

CTLA-4 and PD-1 were significantly upregulated on both HPV+ and HPV- HNSCC patients' TIL, whereas PD-1+ CD8+ cells were significantly enriched in TIL from HPV+ patients (p=0.006). Interestingly, PD-1high cells represented a more dysfunctional phenotype, with severely compromised IFN-γ secretion (phigh CD8+ TIL were more likely to be HPV- and had a worse disease free survival (HR = 2.25; 95% CI = 1.46 – 3.15; p < .0001), while high fractions of PD-1low T cells were associated with better clinical outcome (HR= 0.19, 95% CI = .07 - .49, p = .0006), and were seen preferentially in HPV+ HNSCC patients. In the murine HNSCC model, anti-PD-1 mAb plus radiotherapy resulted in optimal tumor elimination, which was associated with an elimination of PD-1high CD8+ T cells and – most importantly – increase in PD-1low/intermed T cell frequencies (p < 0.5).

Discussion

Consideration of different PD-1 expression levels on TIL segregates PD-1 expression as a marker of activated, competent tumor reactive T cells on the one hand (low/intermed expression), and as a marker of exhausted, dysfunctional cells in the tumor microenvironment on the other hand (high expression). These results emphasize the crucial role of differential PD-1 expression levels on HNSCC patients' effector T cells for prognosis and as a potential novel biomarker for anti-PD-1/PD-L1 based immunotherapy.

Authors’ Affiliations

(1)
Department of Otorhinolaryngology, University Hospital Essen, Germany, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
(2)
University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
(3)
Biostatistics Facility, University of Pittsburgh Cancer Institute, Pittsburgh, Pittsburgh, PA, USA
(4)
Department of Otorhinolaryngology, University Hospital Essen, Germany, Essen, Germany
(5)
Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pittsburgh, PA, USA
(6)
Dana-Farber/Harvard Cancer Center, Boston, MA, USA
(7)
Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

Copyright

© Kansy 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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