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Interspatial Distribution of Tumor and Immune Cells in Correlation with PD-L1 in Molecular Subtypes of Gastric Cancers

Institute of Pathology, University of Bern, 3008 Bern, Switzerland
Institute of Pathology, Cantonal Hospital Baselland, 4410 Liestal, Switzerland
Department of Visceral Surgery and Medicine, Inselspital Bern, University of Bern, 3010 Bern, Switzerland
Institute of Clinical Pathology and Molecular Pathology, Kepler University Hospital, Johannes Kepler University, 4021 Linz, Austria
Author to whom correspondence should be addressed.
Academic Editor: David Wong
Cancers 2022, 14(7), 1736;
Received: 8 March 2022 / Accepted: 24 March 2022 / Published: 29 March 2022
(This article belongs to the Special Issue Feature Paper from Journal Reviewers)
The majority of gastric cancers are negative for the Epstein–Barr virus (EBV) and mismatch repair-proficient, or microsatellite stable. Molecular subtyping currently does not influence clinical decision making, and accurate response prediction towards immunotherapy remains a major challenge. We therefore analyzed PD-L1 expression, tumor-infiltrating lymphocytes, and their spatial relationship to tumor cells in EBV-negative mismatch repair-proficient gastric cancers compared to EBV-positive and mismatch repair-deficient tumors to identify an immunogenic phenotype that is susceptible to immunotherapy in this large group. We demonstrated a close relationship between the total number of tumor-infiltrating lymphocytes, their proximity to tumor cells, and the expression of PD-L1 across all subtypes, including the EBV-negative and mismatch repair-proficient cancers. However, we also identified a subgroup of PD-L1-negative, EBV-negative, and mismatch repair-proficient cancers with high numbers of tumor-associated CD8+ lymphocytes. This is indicative of an immunoreactive phenotype in a subgroup of gastric cancers along or independent of PD-L1 status and molecular type.
(1) Background: EBV-positive and mismatch repair-deficient (MMRd) gastric cancers (GCs) show higher levels of tumor-infiltrating lymphocytes (TILs) and PD-L1 expression and thus a more profound response to immunotherapy. However, the majority of GCs are EBV-negative (EBV−) and MMR proficient (MMRp). We analyzed PD-L1 expression and TILs in EBV-MMRpGCs in comparison to EBV-positive (EBV+) and MMRdGCs to identify an immunogenic phenotype susceptible to immunotherapy. (2) Methods: A next-generation tissue microarray of 409 primary resected GCs was analyzed by Epstein-Barr encoding region (EBER) in situ hybridization for MSH1, PMS2, MSH2, MSH6, PD-L1, and CD8 immunohistochemistry. PD-L1 positivity was defined as a combined positive score (CPS) of ≥1. CD8+ TILs and their proximity to cancer cells were digitally analyzed on the HALO™ image analysis platform. (3) Results: Eleven cases were EBV+, 49 cases MMRd, and 349 cases EBV-MMRpGCs. The highest rate of PD-L1 positivity was seen in EBV+GCs, followed by MMRdGCs and EBV-MMRpGCs (81.8%, 73.5%, and 27.8%, respectively). EBV+ and MMRdGCs also demonstrated increased numbers and proximity of CD8+ TILs to tumor cells compared to EBV-MMRpGCs (p < 0.001 each). PD-L1 status positively correlated with the total numbers of CD8+ TILs and their proximity to tumor cells in all subtypes, including EBV-MMRpGCs (p < 0.001 each). A total of 28.4% of EBV-MMRpGCs showed high CD8+ TILs independent of PD-L1. (4) Conclusions: PD-L1 and CD8 immunohistochemistry, supplemented by digital image analysis, may identify EBV-MMRpGCs with high immunoreactivity indices, indicating susceptibility to immunotherapy. View Full-Text
Keywords: gastric cancer; PD-L1; TIL; EBV; MMR; MSI; immunotherapy gastric cancer; PD-L1; TIL; EBV; MMR; MSI; immunotherapy
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MDPI and ACS Style

Dislich, B.; Mertz, K.D.; Gloor, B.; Langer, R. Interspatial Distribution of Tumor and Immune Cells in Correlation with PD-L1 in Molecular Subtypes of Gastric Cancers. Cancers 2022, 14, 1736.

AMA Style

Dislich B, Mertz KD, Gloor B, Langer R. Interspatial Distribution of Tumor and Immune Cells in Correlation with PD-L1 in Molecular Subtypes of Gastric Cancers. Cancers. 2022; 14(7):1736.

Chicago/Turabian Style

Dislich, Bastian, Kirsten D. Mertz, Beat Gloor, and Rupert Langer. 2022. "Interspatial Distribution of Tumor and Immune Cells in Correlation with PD-L1 in Molecular Subtypes of Gastric Cancers" Cancers 14, no. 7: 1736.

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