Immunophenotype based on inflammatory cells, PD-1/PD-L1 signalling pathway and M2 macrophages predicts survival in gastric cancer

Abstract

Background Immune response against cancer has prognostic impact but its role in gastric cancer is poorly known. The aim of the study was to assess the prognostic significance of immune cell score (CD3+, CD8+), tumour immune escape (PD-L1, PD-1) and immune tolerance (Clever-1). Methods After exclusion of Epstein-Barr virus positive (n = 4) and microsatellite instable (n = 6) tumours, the study included 122 patients with GC undergoing D2 gastrectomy. CD3+ and CD8+ based ICS, PD-L1, PD-1 and Clever-1 expressions were evaluated. Differences in survival were examined using Cox regression adjusted for confounders. The primary outcome was 5-year survival. Results The 5-year overall survival rate was 43.4%. High ICS was associated with improved overall survival (adjusted HR 0.48 (95% CI 0.26–0.87)) compared to low ICS. In the high ICS group, patients with PD-L1 expression (5-year survival 69.2 vs. 53.1%, p = 0.317), high PD-1 (5-year survival 70.6 vs. 55.3% p = 0.312) and high Clever-1 (5-year survival 72.0% vs. 45.5% (p = 0.070) had poor prognosis. Conclusions High ICS was associated with improved survival. In the high ICS group, patients with high PD-L1, PD-1 and Clever-1 had poor prognosis highlighting the importance of immune escape and immune tolerance in GC.

NF-κB in Gastric Cancer Development and Therapy

“…The expression of PD-L1 in resected tissue (43.6% of samples) was related to a less advanced stage, intestinal type, and well/moderately differentiated adenocarcinoma, as well as to a better disease-free survival of patients with GC [ 94 ]. In contrast, Junttila et al [ 95 ] demonstrated that the recruitment of CD3+ and CD8+ immune cells in tumors was associated with an improved overall survival, but PD-L1 expression in these tumors was associated with poor prognosis for patients with GC. Whether the immune checkpoint molecules are promising targets for the immunotherapy of gastrointestinal cancers is still under investigation [ 129 ].…”

“…It has been shown that TAMs-released TNF and IL-6 influence the expression of programmed-death ligand 1 (PD-L1) in gastric tumor cells via NF-κB and STAT3 signaling, thereby promoting the proliferation of GC cells [ 127 ]. PD-L1 on tumor cells is the ligand for T-cells-expressed programmed death 1 (PD-1), and it is one of the so-called immune checkpoint molecules, which can dump cytotoxic T-cell response towards tumors [ 95 ]. The human PD-L1 promoter encompasses potential NF-κB binding sites, but in addition to gene transcription, NF-κB signaling pathways can participate in the regulation of PD-L1 level via regulating other mediators [ 128 ].…”

Clever-1 positive macrophages in breast cancer

“…They associate with a worse prognosis in bladder carcinoma [21][22][23] and predict metastasis and risk of recurrence in oral cavity squamous cell carcinoma [24]. Clever-1 + macrophages in gastric cancer predict worse prognosis in tumors with a high T-lymphocyte count [25] or in early stage tumors [26]. High numbers of peritumoral Clever-1 + macrophages in colorectal carcinomas correlate with a better prognosis in early stages, but in the metastatic stage, high intratumoral counts correlate with a worse prognosis [27].…”

Validity of novel techniques (modified tissue ELISA and IHC) in correlation and comparison for detection of patients with gastric cancer using cut off values of check point inhibitor (PD-1 & PD-L1)

“…Furthermore, PD-L1 expression in tumor cells has been reported in 14-24% of patients with gastro-oesophageal cancer. There are several ongoing studies in phase 1-3 with various combinations and different settings against PD-L1 positive gastric cancer (Junttila, A., et. al., 2020).…”