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

Abstract

We examined the prognostic value of programmed cell death-1 (PD-1) and its ligand (PD-L1) together with CD8+ tumor-infiltrating lymphocytes (TILs) and FOXP3+ Tregs in resectable pancreatic ductal adenocarcinoma (PDAC) samples treated with adjuvant chemotherapy. Whole-mount FFPE tissue sections from 145 pancreatectomies were immunohistochemically stained for PD-1, PD-L1, CD8 and FOXP3. Their expression was correlated with clinicopathological characteristics, and overall survival (OS), progression-free survival (PFS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS), in the context of stroma density (haematoxylin-eosin) and activity (alpha-smooth muscle actin) and in regard to intratumoral lymphoid aggregates. The median OS was 21 months after a mean follow-up of 20 months (range, 2-69 months). In multivariate analysis, high PD-1+ TILs expression was associated with better OS (p = 0.049), LPFS (p = 0.017) and DMFS (p = 0.021). Similar findings were observed for CD8+ TILs, whereas FOXP3 and PD-L1 lacked prognostic significance. Although TIL distribution was heterogeneous, tumors of high stroma density had higher infiltration of CD8+ TILs than loose density stroma and vice versa (p < 0.001), whereas no correlation was found with stromal activity. Sixty (41.4%) tumors contained lymphoid aggregates and the presence of PD-1+ TILs was associated with better OS (p = 0.030), LPFS (p = 0.025) and DMFS (p = 0.033), whereas CD8+ TILs only correlated with superior LPFS (p = 0.039). PD-1+ and CD8+ TILs constitute independent prognostic markers in patients with PDAC treated with adjuvant chemotherapy. Our study provides important insight on the role of PD-1/PD-L1 in the context of desmoplastic stroma and could help guide future immunotherapies in PDAC.

Role of immune microenvironment in gastrointestinal stromal tumours

“…This result may be reflective of a more robust immune response to the tumour that at least partially mitigates the more aggressive behavior seen in PD‐L1/IDO positive tumours . This favorable association is in line with previous literature showing an association between CD3 + and CD8 + TILs and improved outcomes of other solid tumours such as breast or pancreatic cancer …”

“…Accumulating evidence suggests a correlation between tumour‐infiltrating lymphocyte (TIL) counts in cancer tissue and favorable prognosis in various malignancies. In particular, the presence of CD8 + T‐cells and the ratio of CD8 + effector T‐cells to FoxP3 + regulatory T‐cells (T regs ) appear to correlate with improved prognosis and long‐term survival in solid tumours . The PD‐1/PD‐L1 interaction is a major pathway that has been shown to be altered by tumours in order to suppress immune recognition and control.…”

Serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death ligand 1 (sPD-L1) in advanced pancreatic cancer

“…25 While sPD-L1 has not been determined in PC before, conflicting findings on the prognostic relevance of membrane bound PD-L1 on PC tumor cells exist. 7,35 Using a cox regression model including established prognostic factors for patients with advanced PC, we did not find an adverse influence of sPD-1 or sPD-L1 on OS. Likewise, we did not find a significant survival difference between patients with high vs. low sPD-1 or sPD-L1, respectively.…”

“…This is in line with the recent report on the absent prognostic effect of PD-L1 expression on PC tumor cells and the rather disappointing early trial results of checkpoint blockade as monotherapy in advanced PC and could suggest that PD-L1 blockade alone might possibly not be sufficient to improve prognosis in advanced PC patients. [35][36][37] Serum CA 19-9 and CEA are established tumor markers in PC. [19][20][21][22] Higher CA 19-9 and CEA levels indicate higher tumor burden and poor outcome.…”

Local immune parameters as potential predictive markers in head and neck squamous cell carcinoma patients receiving induction chemotherapy and cetuximab

“…Our finding of increased amount of PD‐1 + lymphocytes in tumors of responding patients is interesting because, although PD‐1 is classified as a marker of T‐cell exhaustion, it has also been proved an activation marker expressed predominantly by tumor‐reactive infiltrating T cells . There are conflicting results on the prognostic effect of PD‐1 expression by tumor‐infiltrating immune cells, with negative effect in the case of renal and breast carcinomas while positive one in others, as ovarian, pancreatic, colorectal, and lung cancer . High level of PD‐1 expression was detected in HNSCC TILs, and their amount proved a favorable prognostic marker .…”