PD-L1 and immune infiltrates are differentially expressed in distinct subgroups of gastric cancer

Abstract

This study investigates the association of PD-L1 expression and immune cell infiltrates and their impact on clinical outcome, in addition to their overlap with microsatellite instability (MSI), HER2 and ATM molecular subgroups of gastric cancer (GC). PD-L1 membrane expression on tumour cells (TC) and infiltrating immune cells (IC), CD3 + T-lymphocytes, CD8+ cytotoxic T-cells, ATM and HER2 were assessed by immunohistochemistry (IHC) in the ACRG (Asian Cancer Research Group) GC cohort (N = 380). EBV status was determined using in situ hybridization and MSI status was performed using PCR and MLH1 IHC. The PD-L1 segment was associated with increased T-cell infiltrates, while the MSI-high segment was enriched for PD-L1, CD3, and CD8. Multivariate analysis confirmed PD-L1 positivity, high CD3 and high CD8 as independent prognostic factors for both disease-free survival and overall survival (all p < 0.05). Patients with MSI-high tumours had better overall survival by both univariate and multivariate analysis. The ATM-low and HER2-high subgroups differed markedly in their immune profile; the ATM-low subgroups enriched for MSI, PD-L1 positivity and CD8 + T-cells, while the HER2 segment was enriched for MSS, with no enrichment for immune markers. Hence, we demonstrate a molecular profiling approach that can divide GC into four molecular subgroups, namely ATM-low, HER2-high, PD-L1 positive and MSI-high with differing levels of immune infiltrates and prognostic significance which may help to stratify patients for response to targeted therapies.

Osteosarcoma and soft-tissue sarcomas with an immune infiltrate express PD-L1: relation to clinical outcome and Th1 pathway activation

“…28 Previous studies in various cancer types including sarcomas have reported conflicting results on the relationship between PD-L1 tumor expression and clinical outcome, however, studies of a variety of malignancies coincided with our finding that high PD-L1 expression was associated with significantly better survival. 11,12,[29][30][31][32][33] One explanation may lie in which cell types express PD-L1, and to what degree. We found that, although a proportion of UPS and MFS patients has tumors that contain TILs and express PD-L1, better survival was associated with high PD-L1 expression in UPS and OSA; we did not detect any association with survival in MFS.…”

<p>Integrated assessment of PD-L1 expression and molecular classification facilitates therapy selection and prognosis prediction in gastric cancer</p>

“…Two gastrointestinal pathologists reviewed all H&E slides, immunohistochemical, and in situ hybridization slides, with no previous knowledge of the clinical or pathological parameters. The detailed procedure for immunohistochemical analysis was performed according to descriptions in prior studies and the concrete evaluation was as follows:8,9,27 A tumor was taken as d-MMR if at least one of the markers (MLH1, MSH2, MSH6, and PMS2) showed a complete loss of nuclear reactivity in conjunction with appropriate retention in background nonmalignant cells. Complete loss of membranous reactivity or reserved membranous staining less than 70% were regarded as aberrant E-cadherin expression, irrespective of whether or not they were accompanied with cytoplasmic or nuclear expression.…”

MSI as a predictive factor for treatment outcome of gastroesophageal adenocarcinoma

“…The generally good prognostic outcome may be related to immunosurveillance; MSI-H gastroesophageal tumors are characterized by high levels of CD8 positive T-cells infiltrate [48]. This, in turn, can also explain the favorable response of MSI-H gastroesophageal cancer patients to checkpoint blockade.…”