A comprehensive analysis of tumor-stromal collagen in relation to pathological, molecular, and immune characteristics and patient survival in pancreatic ductal adenocarcinoma

Background: Abundant collagen deposition is a hallmark of pancreatic ductal adenocarcinomas (PDACs). This study clarified the interactive relationship between tumor-stromal collagen, molecular and immune characteristics, and tumor pr ogression in human PDAC.

Methods: We performed a comprehensive examination using an integrative molecular pathological epidemiology database on 169 cases with resected PDAC . The amount of tumor-stromal collagen was quantified through digital imaging analysis for Elastica van Gieson-stained whole-section tumor slides. We analyzed the association of tumor-stromal collagen with gene alterations (KRAS, TP53, CDKN2A/p16, and SMAD4), immune parameters (CD4⁺ tumor-infiltrating lymphocytes [TILs], CD8⁺ TILs, FOXP3⁺ TILs, and tertiary lymphoid structures), and patient prognosis.

Results: Low amounts of tumor-stromal collagen were associated with poor differentiation (multivariable OR = 3.82, 95%CI = 1.41-12.2, P = 0.008) and CDKN2A/p16 alteration (OR [95%CI] = 2.06 [1.08-4.02], P = 0.03). Tumors with low collagen levels had shorter overall survival (HR [95%CI] = 2.38 [1.59-3.56], P < 0.0001). In the S-1 and gemcitabine (GEM) treatment groups, low tumor-stromal collagen was linked to poor prognosis of patients with PDAC (S-1 group: multivariable HR [95%CI] = 2.76 [1.36-5.79], P = 0.005; GEM group: multivariate HR [95%CI] = 2.91 [1.34-6.71], P = 0.007). Additionally, low amounts of tumor-stromal collagen were also linked to low levels of CD4⁺ TILs (P = 0.046), CD8⁺ TILs (P = 0.09), and tertiary lymphoid structures (P = 0.001).

Conclusions: Tumor-stromal collagen deposition may play a crucial role in modulating tumor-immune microenvironment and determining response to adjuvant chemotherapy and patient survival outcomes.