Immunologic and Metabolic Features of Pancreatic Ductal Adenocarcinoma Define Prognostic Subtypes of Disease

Abstract

Purpose Pancreatic ductal adenocarcinoma (PDA) is associated with an immunosuppressive microenvironment that supports the growth of the malignancy as well as immune system evasion. Here we examine markers of immunosuppression in PDA within the context of the glycolytic tumor microenvironment, their inter-relationship with tumor biology and association with overall survival. Experimental design We utilized tissue microarrays consisting of 223 PDA patients annotated for clinical stage, tumor size, lymph node involvement, and survival. Expression of CD163, FoxP3, PD-L1, and MCT4 was assessed by immunohistochemistry and statistical associations were evaluated by univariate and multivariate analysis. Multi-marker subtypes were defined by Random Forest analysis. Mechanistic interactions were evaluated using PDA cell lines and models for myeloid differentiation. Results PDA exhibits discrete expression of CD163, FoxP3 and PD-L1 with modest individual significance. However, combined low expression of these markers was associated with improved prognosis (P =0.02). PDA tumor cells altered macrophage phenotype and function, which supported enhanced invasiveness in cell-based models. Lactate efflux mediated by MCT4 was associated with, and required for, the selective conversion of myeloid cells. Correspondingly, MCT4 expression correlated with immune markers in PDA cases, and increased the significance of prognostic subtypes (P = 0.002). Conclusions There exists a complex interplay between PDA tumor cells and the host immune system wherein immunosuppression is associated with negative outcome. MCT4 expression, representative of the glycolytic state of PDA, contributes to the phenotypic conversion of myeloid cells. Thus, metabolic status of PDA tumors is an important determinant of the immunosuppressive environment.

Stratification of Pancreatic Ductal Adenocarcinoma: Combinatorial Genetic, Stromal, and Immunologic Markers

“…In contrast, the presence of macrophages (CD68 positive) and in particular M2 macrophages (CD163 positive) had negative effect on survival. These data are consistent with an emerging literature that the presence of tumor-associated macrophages (TAMs) is associated with more aggressive form of disease(40, 48). In addition to supporting tumor invasiveness and metastatic spread, TAMs inhibit T cell responses by production of indoleamine dioxygenase metabolites and reactive oxygen species and indirectly by recruiting regulatory T-cells to the tumor (49, 50).…”

Prognostic value, localization and correlation of PD-1/PD-L1, CD8 and FOXP3 with the desmoplastic stroma in pancreatic ductal adenocarcinoma

“…Traditionally, the abundant desmoplastic stroma has been regarded as a barrier impairing tumor infiltration by TILs [3, 4]. Ino et al previously reported better outcome in patients with high stromal expression of CD8 [11], which is in agreement with our data but a recent work failed to detect a prognostic role for CD8+ TILs [32]. Also, even in tumors with high CD8+ TILs infiltration in the stroma, the majority of tumors lacked CD8+ TILs in the close proximity to cancer cells in our cohort.…”

“…Although work have assessed the prognostic impact of TILs and Tregs, and recently of PD-L1 [32], in PDAC, nevertheless, none of these studies examined in detail the association of all four immune markers with the desmoplastic stoma and their localization in large pancreatectomy sections. Traditionally, the abundant desmoplastic stroma has been regarded as a barrier impairing tumor infiltration by TILs [3, 4].…”

Metabolic Interactions in the Tumor Microenvironment

“…In melanoma, lactate suppresses natural killer and T cell anti-tumor immune responses [20, 101, 102]. Similarly, tumor-derived lactate drives macrophages toward an immunosuppressive fate [21, 103, 104]. In these contexts, lactate functions directly as a signaling molecule, though the contribution of lactate in this capacity relative to its role in metabolic pathway rewiring and microenvironment acidification have yet to be fully elucidated.…”