Aim:
Remodelling of the PDAC microenvironment and ECM has been implicated in the prognosis
of PDAC. We investigated whether infiltration of immune cell-subsets (CD3, CD4, CD8,
CD68, CD206 or neutrophils) affect the survival of pancreatic cancer patients and
affect stromal composition (fibrogenic (αSMA high/collagen I high) versus fibrolytic
stroma (αSMA high/collagen I low)) and aimed at finding of a comprehensive prognostic
signature.
Material & Methods:
TMAs of 404 patients from the ESPAC-3 trial undergoing adjuvant chemotherapy were
immunostained for αSMA, collagen-I, CD3, CD4, CD8, CD68, CD206 and neutrophils. H-Scores
of individual staining were calculated for each core by multiplying the integrated
density of tumor cell staining. A median H-Score was calculated for all cores from
each patient. Event free survival was plotted against low/high expression of immune
cell-subsets using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards
models. All statistical tests were two-sided and were performed in R.
Results:
In 1824 TMA from 382 patients (94.6%) immune cell composition was distinctly different
in fibrolytic versus fibrogenic stroma. Median event free survival (EFS) for patients
with high CD3 expression as a single marker was 14.3 months (95% CI 12.7 to 17.3)
whereas low CD3 expression predicted significantly decreased survival (11 months,
95% CI 9.9 to 12.7, χ2
LR,1DF= 14.7; P = 0.0001). CD8, CD68 and CD206 expression showed similar trends. Recursive
partitioning for discrete-time-survival-tree analysis showed dependence of leukocyte
subpopulations in determining fibrogenic vs. fibrolytic stroma and median EFS varied
between 6.3 month versus 20.1 month depending on immune cell infiltration and type
of stroma.
Discussion:
The comprehensive prognostic signature based on interaction of immune cell infiltration
with stromal composition for resected pancreatic ductal adenocarcinoma provides better
stratification in predicting event free survival. Immune cells determine the predominant
type of stromal composition and this may help in understanding the effect of the host
immune response.