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Poster Presentation
Level of PD-1 expression on CD8+ T cells influence prognosis and respond to PD-1 therapy in a murine model
  1. Benjamin A Kansy1,
  2. Raghvendra M Srivastava2,
  3. Hyun-Bae Jie2,
  4. Gulidanna Shayan2,
  5. Yu Lei2,
  6. Jing Li2,
  7. William Gooding3,
  8. Sven Brandau4,
  9. Stephan Lang4,
  10. Nicole Schmitt5,
  11. Gordon J Freeman6,
  12. David A Clump7 and
  13. Robert L Ferris2
  1. Aff1 grid.21925.3d0000000419369000Department of Otorhinolaryngology, University Hospital Essen, GermanyUniversity of Pittsburgh Cancer Institute Pittsburgh PA USA
  2. Aff2 grid.21925.3d0000000419369000University of Pittsburgh Cancer Institute Pittsburgh PA USA
  3. Aff3 grid.21925.3d0000000419369000Biostatistics FacilityUniversity of Pittsburgh Cancer Institute Pittsburgh, Pittsburgh PA USA
  4. Aff4 grid.410718.b0000000102627331Department of OtorhinolaryngologyUniversity Hospital Essen Germany, Essen Germany
  5. Aff5 grid.21925.3d0000000419369000Department of OtolaryngologyUniversity of Pittsburgh Pittsburgh, Pittsburgh PA USA
  6. Aff6 grid.48336.3a0000000419368075Dana-Farber/Harvard Cancer Center Boston MA USA
  7. Aff7 grid.21925.3d0000000419369000Department of Radiation OncologyUniversity of Pittsburgh Cancer Institute Pittsburgh PA USA

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

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    Meeting abstracts

    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.