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. 2018 Jun;7(6):2612-2620.
doi: 10.1002/cam4.1502. Epub 2018 Apr 19.

Programmed death-ligand 1 expression in gastric cancer: correlation with mismatch repair deficiency and HER2-negative status

Lei Wang  1   2 , Qiongyan Zhang  1   2 , Shujuan Ni  1   2 , Cong Tan  1   2 , Xu Cai  1   2 , Dan Huang  1   2 , Weiqi Sheng  1   2
Affiliations

Programmed death-ligand 1 expression in gastric cancer: correlation with mismatch repair deficiency and HER2-negative status

Lei Wang et al. Cancer Med. 2018 Jun.

Abstract

Gastric cancer (GC) is one of the most common malignancies. Immunotherapy is a promising targeted treatment. The immune regulatory programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis has been used as a checkpoint target for immunotherapy. Currently, considerable discrepancies exist concerning the expression status of PD-L1 and its prognostic value in GC. We aimed to evaluate the expression rates of PD-L1 in GC, and further assess its relationship with mismatch repair (MMR), and human epidermal growth factor receptor 2 (HER2) status. We retrospectively collected 550 consecutive cases of GC in Fudan University Shanghai Cancer Center from 2010 to 2012. PD-L1, MMR protein, and HER2 status were detected by immunohistochemistry (IHC). Fluorescence in situ hybridization was further used in HER2 IHC 2+ cases. Cases with at least 1% membranous and/or cytoplasmic PD-L1 staining in either tumor cells (TCs) or tumor-infiltrating immune cells (TIICs) were considered as PD-L1 positive. The correlation between clinicopathological parameters, HER2, MMR, and PD-L1 expression status was determined using chi-squared tests. About 37.3% cases (205/550) showed PD-L1 expression in TCs and/or TIICs. 17.3% cases (95/550) showed PD-L1 expression in TCs, 34.5% (190/550) cases showed PD-L1 expression in TIICs. There were 45 deficient MMR (dMMR) cases (8.2%), which showed higher rates of PD-L1 expression compared with MMR-proficient carcinomas (60.0% vs. 35.2%, P = 0.001). HER2 was positive in 66 (12.0%) cases. The expression of PD-L1 occurred more frequently in HER2-negative group than HER2-positive cohorts (39.0% vs. 24.2%, P = 0.020). The survival analysis revealed that PD-L1 was not associated with prognosis. This study evaluated the association between the PD-L1 expression and a specific subgroup (dMMR and HER2-negative) in a large Asian cohort of GC. GC patients with dMMR and HER2-negative status exhibited higher PD-L1 expression rates. Our finding indicated that MMR and HER-2 status might be potential biomarkers for anti-PD-L1 therapy.

Keywords: Gastric cancer; HER2; mismatch repair deficiency; programmed death-ligand 1.

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Figures

Figure 1
Figure 1
Representative images of PD‐L1 immunostaining. PD‐L1 was immunostained on the membrane and/or the cytoplasm of the tumor cells with variable intensities: (A) weak (score 1), (B) moderate (score 2), (C) strong (score 3). (D) PD‐L1 was immunostained only in tumor‐infiltrated immune cells. (E) PD‐L1 expression was detected in both tumor cells and tumor‐infiltrating immune cells.
Figure 2
Figure 2
Deficient MMR GCs tend to show positive PD‐L1 expression. In this cases (A, HE), PD‐L1 expressed mainly in the tumor cells (B). MLH1 and PMS were negative (C, D), and MSH2 and MSH6 are positive (E, F).
Figure 3
Figure 3
Kaplan–Meier plots of disease‐free survival and overall survival according to PD‐L1 expression in tumor cells (A, C) and tumor‐infiltrating immune cells (B, D) in stage II GC patients.
Figure 4
Figure 4
Kaplan–Meier plots of disease‐free survival and overall survival according to PD‐L1 expression in tumor cells (A, C) and tumor‐infiltrating immune cells (B, D) in stage III and IV GC patients.
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