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. 2016 Nov 14:6:36956.
doi: 10.1038/srep36956.

PD-L1 expression on immune cells, but not on tumor cells, is a favorable prognostic factor for head and neck cancer patients

Hye Ryun Kim  1 , Sang-Jun Ha  2 , Min Hee Hong  1 , Su Jin Heo  1 , Yoon Woo Koh  3 , Eun Chang Choi  3 , Eun Kyung Kim  4 , Kyoung Ho Pyo  5 , Inkyung Jung  6 , Daekwan Seo  7 , Jaewoo Choi  7 , Byoung Chul Cho  1   5 , Sun Och Yoon  4
Affiliations

PD-L1 expression on immune cells, but not on tumor cells, is a favorable prognostic factor for head and neck cancer patients

Hye Ryun Kim et al. Sci Rep. .

Abstract

To investigate the expression of programmed death-ligand 1 (PD-L1) and immune checkpoints and their prognostic value for resected head and neck squamous cell cancer (HNSCC). PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (IC), abundance of tumor-infiltrating lymphocytes (TILs), and expression of the immune checkpoints were investigated in 402 HNSCC patients. PD-L1 expression on TC and IC was categorized into four groups according to the percentage of PD-L1-positive cells. PD-L1 positivity was defined as ≥5% of cells based on immunohistochemistry. High PD-L1 expression on IC, but not TC, was an independent favorable prognostic factor for RFS and OS adjusted for age, gender, smoking, stage, and HPV. High frequencies of CD3+ or CD8+ TILs, Foxp3+ Tregs, and PD-1+ TILs were strongly associated with favorable prognosis. PD-L1 was exclusively expressed on either TC or IC. Transcriptome analysis demonstrated that IC3 expressed higher levels of the effector T cell markers than TC3, suggesting that PD-L1 expression is regulated via an adaptive IFNγ-mediated mechanism. High PD-L1 expression on IC, but not TC, and high abundance of PD-1+ T cells and Foxp3+ Tregs are favorable prognostic factors for resected HNSCC. This study highlights the importance of comprehensive assessment of both TC and IC.

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Figures

Figure 1
Figure 1
(A) A representative sample showing CD3+, CD8+, and regulatory T cells: (a) low infiltration of CD3+ T cells (b) high infiltration of CD3+ T cells (c) low infiltration of CD8+ T cells (d) high infiltration of CD8+ T cells (e) low infiltration of Foxp3+ Tregs (f) high infiltration of Foxp3+ Tregs. (B) A representative sample showing the expression of immune regulatory receptors on immune cells: (a) low expression of PD-1 (b) high expression of PD-1 (c) low expression of LAG-3 (d) high expression of LAG-3 (e) low expression of ICOS (f) high expression of ICOS. (C) PD-L1 expression was semi-quantitatively graded in tumor-infiltrating immune cells (IC) as IC0, 0% (a); IC1, >0% but <5% (b); IC2, ≥5% but <50% (c); and IC3 ≥50% (d). In tumor cells (TC), PD-L1 expression was graded as TC0, 0% (e); TC1, >0% but <5% (f); TC2, ≥5% but <50% (g); and TC3, ≥50% (h).
Figure 2
Figure 2. The 402 included patients were assigned to one of two groups based on specific subsets of T lymphocytes.
(A) The 5-year RFS rate was 65.0% for low CD3+ vs. 79.1% for high CD3+; P = 0.005. (B) The 5-year OS rate was 73.5% for low CD3+ vs. 86.3% for high CD3+; P = 0.01. (C) The 5-year RFS rate was 63.3% for low CD8+ vs. 80.7% for high CD8+; P < 0.0001. (D) The 5-year OS rate was 72.4% for low CD8+ vs. 87.1% for high CD8+; P = 0.003. (E) The 5-year RFS rate was 64.7% for low Foxp3 Treg vs. 79.5% for high Foxp3 Treg; P = 0.05. (F) The 5-year OS rate was 74.8% for low Foxp3 Treg vs. 84.9% for high Foxp3 Treg; P = 0.09.
Figure 3
Figure 3
(A) The 5-year recurrence-free survival (RFS) rate was 72.4% for PD-L1-positive tumor cells (TC) vs. 65.6% for PD-L1-negative TC; P = 0.206. (B) The 5-year overall survival (OS) rate was 80.1% for PD-L1-positive TC vs. 77.7% for PD-L1-negative TC; P = 0.317. (C) The 5-year RFS rate was 69.7% for PD-L1-negative immune cells (IC) vs. 80.1% for PD-L1-positive IC; P = 0.005. (D) The 5-year OS rate was 75.6% for PD-L1-negative IC vs. 90.6% for PD-L1-positive IC; P = 0.003. (E) PD-L1 expression on TC and IC was categorized into four groups according to the percentage of positive cells: TC0 or IC0, 0%; TC1 or IC1, >0% but <5%; TC2 or IC2, ≥5% but <50%; and TC3 or IC3, ≥50%. The counts (frequencies) of TC1/2/3 and IC1/2/3 were 129/402 (32.1%) and 201/402 (50%), respectively, and the overlap between TC1/2/3 and IC1/2/3 was 103/402 (25.6%). The counts (frequencies) of TC2/3 and IC2/3 were 73/402 (18.2%) and 112/402 (27.9%), and the overlap between these two groups was 40/402 (10%). Notably, the counts (frequencies) of TC3 and IC3 were 10/402 (2.5%) and 28/402 (7.0%), respectively, and the overlap between TC3 and IC3 was only 1/402 (0.2%).
Figure 4
Figure 4. The 402 included patients were assigned to one of two groups based on immune checkpoint expression on T lymphocytes.
(A) The 5-year RFS rate was 82.1% for PD-1+ T cells vs. 68.3% for PD-1− T cells (P = 0.02). (B) The 5-year OS rate was 88.8% for PD-1+ T cells vs. 76.9% for PD-1− T cells (P = 0.06). (C) The 5-year RFS rate was 77.1% for LAG-3+ T cells vs. 67.1% for LAG-3− T cells (P = 0.054). (D) The 5-year OS rate was 83.9% for LAG-3+ T cells vs. 75.7% for LAG-3− T cells (P = 0.16). (E) The 5-year RFS rate was 75.2% for ICOS+ T cells vs. 69.9% for ICOS− T cells (P = 0.53). (F) The 5-year OS rate was 79.9% for ICOS+ T cells vs. 80.0% for ICOS− T cells (P = 0.64).
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