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Article

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

1
Institute of Pathology, University of Bern, 3008 Bern, Switzerland
2
Institute of Pathology, Cantonal Hospital Baselland, 4410 Liestal, Switzerland
3
Department of Visceral Surgery and Medicine, Inselspital Bern, University of Bern, 3010 Bern, Switzerland
4
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; https://doi.org/10.3390/cancers14071736
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. https://doi.org/10.3390/cancers14071736

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. https://doi.org/10.3390/cancers14071736

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. https://doi.org/10.3390/cancers14071736

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