Prognostic Significance of Tumor-Infiltrating Lymphocytes in Patients With Pancreatic Ductal Adenocarcinoma Treated With Neoadjuvant Chemotherapy

Abstract

Objectives To examine tumor infiltrating lymphocytes (TILs) and their prognostic value in patients with pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant therapy. Methods Intra-tumoral CD4+, CD8+, and FOXP3+ lymphocytes was examined by immunohistochemistry using a computer-assisted quantitative analysis in 136 PDAC patients who received neoadjuvant therapy and pancreaticoduodenectomy. The results were correlated with clinicopathologic parameters and survival. Results High CD4+ TILs in treated PDAC were associated with high CD8+ TILs (P = 0.003), differentiation (P = 0.04) and a lower frequency of recurrence (P = 0.02). Patients with high CD4+ TILs had longer disease-free survival (DFS) and overall survival (OS) than did patients with low CD4+ TILs (P < 0.01). The median OS of patients with a high CD8+/FOXP3+ lymphocyte ratio (39.5 [standard deviation, 6.1] months) was longer than that of patients with a low CD8+/FOXP3+ lymphocyte ratio (28.3 [standard deviation, 2.3] months; P=0.01). In multivariate analysis, high CD4+ TILs were an independent prognostic factor for DFS [Hazard ratio (HR): 0.49, 95% CI, 0.30–0.81; P = 0.005] and OS (HR, 0.54; 95% CI, 0.33–0.89; P = 0.02). Conclusions High CD4+ lymphocytes is associated with tumor differentiation, lower recurrence and is an independent prognostic factor for survival in PDAC patients treated with neoadjuvant therapy.

Prognostic impact of tumour-infiltrating lymphocytes and cancer-associated fibroblasts in patients with pancreatic adenocarcinoma of the body and tail undergoing resection

“…Therefore, the cut‐off value was defined according to the same rule for all biomarkers, independently of the observed associations with the event. The 75th percentile was chosen in line with previous studies.…”

“…Ratios of the different TIL (CD3/CD45, CD4/CD3, CD8/CD3, CD4/CD8, FoxP3/CD3, FoxP3/CD4, FoxP3/CD8) and CAF (αSMA/vimentin) subsets were then calculated. Finally, patients were classified into two groups, low and high ratio, using 75th percentile as the cut‐off value.…”

Neoadjuvant Therapy Remodels the Pancreatic Cancer Microenvironment via Depletion of Protumorigenic Immune Cells

“…Over the past decade, neoadjuvant therapy (neoTx) has dramatically improved prognosis of patients with locally advanced and borderline resectable pancreatic cancer (1,2); thus, understanding its mechanisms of action is of high and immediate clinical relevance. Although traditionally considered to be immunosuppressive, growing evidence suggests that neoTx exerts its beneficial effects by restoration of the local antitumoral immune response (3)(4)(5). Furthermore, neoadjuvant approaches have been shown to enhance systemic immunity and eradicate residual metastasis more effectively than adjuvantly applied regimes on preclinical settings (6,7).…”

Transcriptional and immunohistological assessment of immune infiltration in pancreatic cancer

“…Pancreatic cancer is commonly characterized by extensive desmoplastic stroma and an environment that is poorly supportive of adaptive immune responses, yet like many other cancers, the degree of T cell infiltrate in pancreatic tumors is correlated with patient outcome [1][2][3][4]. T cells in pancreatic tumors face an array of suppressive mechanisms that can limit their ability to control tumors, and it would be beneficial to understand the relationship between T cell infiltration and the presence of other immune populations that positively or negatively regulate immune responses.…”