Prognostic Impact of Tumor-Infiltrating Lymphocytes and Neutrophils on Survival of Patients with Upfront Resection of Pancreatic Cancer

Abstract

In patients with pancreatic ductal adenocarcinoma (PDAC), the tumor microenvironment consists of cellular and stromal components that influence prognosis. Hence, tumor-infiltrating lymphocytes (TILs) may predict prognosis more precisely than conventional staging systems. Studies on the impact of TILs are heterogeneous and further research is needed. Therefore, this study aims to point out the importance of peritumoral TILs, tumor-infiltrating neutrophils (TINs), and immune subtype classification in PDAC. Material from 57 patients was analyzed with immunohistochemistry performed for CD3, CD8, CD20, CD66b, α-sma, and collagen. Hot spots with peritumoral TILs and TINs were quantified according to the QTiS algorithm and the distance of TILs hot spots to the tumor front was measured. Results were correlated with overall (OS) and progression-free survival (PFS). High densities of peritumoral hot spots with CD3+, CD8+, and CD20+ TILs correlated significantly with improved OS and PFS. Combined immune cell subtypes predicted improved OS and PFS. High infiltration of CD3+ TILs predicted progression after 12 months. The location of TILs’ hot spots and their distance to the tumor front did not correlate with patient survival. Peritumoral TILs and the composition of the stroma predict OS and PFS in PDAC.

MMR Deficiency is Homogeneous in Pancreatic Carcinoma and Associated with High Density of Cd8-Positive Lymphocytes

“…Several studies on cohorts from 86 to 214 patients with pancreatic cancer have, in contrast, suggested an association between the fraction of CD8 positive lymphocytes or neutrophils with tumor aggressiveness or clinical outcome of pancreatic cancer. [66][67][68] However, spatial variance of CD8-positive cells-typically between central and peripheral tumor areas-is quite prevalent in pancreatic cancer and may confound analyses when information on the precise localization of the analyzed tumor area is not available. 66 TMA-based studies-at least when TMA construction was not focused on tumor compartments as in our study-may underrepresent the invasive margin that has been shown to confer a prognostic role for CD8-positive cells in pancreatic cancer in particular.…”

“…66 TMA-based studies-at least when TMA construction was not focused on tumor compartments as in our study-may underrepresent the invasive margin that has been shown to confer a prognostic role for CD8-positive cells in pancreatic cancer in particular. 68 Furthermore, pancreatic cancer possess a unique microenvironment characterized by a dense desmoplastic stromal reaction that may enhance regional variability of lymphocytic density. 69 For instance, CD8-positive cells at the invasive margin were significantly associated with overall survival in contrast to the tumor core.…”

E-Cadherin in Pancreatic Ductal Adenocarcinoma: A Multifaceted Actor during EMT

“…Indeed, multiple reports indicate α E (CD103)β 7 interaction with E-cadherin expressed by tumor cells promotes cytolytic T cell activity against different type of tumors such as lung [136] and pancreatic cancer [137]. These data may provide the biological explanation of several clinical data showing that high infiltration of CD8 + lymphocytes correlates with an improved survival in pancreatic cancer patients [138][139][140]. Moreover, it should be noted that CD103 marks also a particular subpopulation of DCs characterized by several functions (i.e., induction of regulatory T cells to maintain tolerance and antigen cross-presentation to CD8 + T cells), playing an important role in immune defense [141][142][143].…”

“…Although not specifically mentioned, it is plausible to hypothesize the involvement of E-cadherin in the generation of MTFs. Second, PDAC is often characterized by lack of infiltration of CD8 + T lymphocytes [152] and, indeed, T cell infiltration is associated with PDAC patient survival [138][139][140]. Different factors can concur in limiting T cell trafficking in the tumor bed and macrophages are one of them [153][154][155].…”

Identification of immune-based prostate cancer subtypes using mRNA expression

“…Macrophages cells as the second proportion (13%) ( Table 1) The prognostic importance of immune cell infiltration for various solid tumor types has been determined [35][36][37]. In univariate and multivariate Cox analysis, only B cell memory was significantly correlated with RFS.…”