P-0035 - Immunosuppressive Protein Expression on Tumor and the Presence of Immune Cells Within Tumor Microenvironment in Curatively Resected Gastric Cancer

Abstract

Introduction: Evading immune destruction is a hallmark of biological capabilities in cancer development. Superficially, the presence of immune cells in tumor microenvironment might be response of host to combat tumors. Immunosuppressive protein on tumor might act to evade host immune surveillance. We evaluated the association among immunosuppressive proteins on tumor and the presence of immune cells in tumor microenvironment and identified their clinical implication. Methods: Of 289 patients with gastric cancer who received curative resection, 243 patients were available for tissue specimens. Expression of programmed cell death 1 ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen 4 (CTLA-4) and indoleamine 2,3-dioxygenase (IDO) on tumor was identified as negative, weak, moderate, or strong staining intensity using immunohistochemistry of tissue microarray. Specimens were recorded as positive when >10% of tumor cells showed moderate to strong staining intensity for PD-L1, CTLA-4 and IDO. The densities of CD3+ and PD-1+ cells within tumor stroma including tumor were assessed using an image analysis system to evaluate the presence of immune cells in tumor microenvironment. Specimens over median density were defined as ‘rich’ group of immune cell in tumor microenvironment. Clinical data and pathologic results were retrieved from electronic medical record. Results: Of 243 patients with gastric cancer, 106 (43.6%), 160 (65.8%) and 116 patients (47.7%) showed positive expression of PD-L1, CTLA-4 and IDO, respectively. The positive expression of PD-L1, CTLA-4 and IDO were frequently showed in less advanced stage (p = 0.047, p = 0.016, p = 0.007, respectively), intestinal type (p = 0.003, p = 0.003, p < 0.001, respectively) and moderate differentiation (p = 0.007, p = 0.011, p = 0.001, respectively). Tumors with CD3+ and PD1+ ‘rich’ microenvironment had the association with diffuse type (p = 0.021, p = 0.058, respectively) and poorly differentiated or signet ring cell type (p = 0.062, p = 0.022, respectively). There was strong correlation among positive expressions of PD-L1, CTLA-4 and IDO on tumor. However, no relationship between expressions of PD-L1, CTLA-4 and IDO on tumor and CD3+ and PD-1+ cell ‘rich’ microenvironment was shown. PD-L1 positive tumor and CD3+ cell ‘rich’ microenvironment had longer disease-free survival and overall survival (p = 0.016, p = 0.006, respectively). In multivariate analysis, these remained better prognostic values (disease-free survival: risk ratio =0.582 (0.372-0.910), p = 0.018, risk ratio = 0.624 (0.399-0.976), p = 0.038, respectively; overall survival: risk ratio= 0.651 (0.416-1.017), p = 0.059, risk ratio= 0.538 (0.347-0.832), p = 0.005, respectively). Conclusion: In gastric cancer, immunosuppressive protein of PD-L1, CTLA-4 or IDO is frequently expressed. Tumors with positive expression of PD-L1, CTLA-4 and IDO and with CD3+ and PD1+ ‘rich’ microenvironment have a distinct clinicopathologic group. There is no relationship between expression of PD-L1, CTLA-4 and IDO on tumor and CD3+ and PD-1+ cell ‘rich’ microenvironment. PD-L1 expression on tumor and CD3+ cell ‘rich’ microenvironment are better prognostic markers independently.