Immunophenotypes of pancreatic ductal adenocarcinoma: Meta‐analysis of transcriptional subtypes

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common malignancy of the pancreas and has one of the highest mortality rates of any cancer type with a 5‐year survival rate of <5%. Recent studies of PDAC have provided several transcriptomic classifications based on separate analyses of individual patient cohorts. There is a need to provide a unified transcriptomic PDAC classification driven by therapeutically relevant biologic rationale to inform future treatment strategies. Here, we used an integrative meta‐analysis of 353 patients from four different studies to derive a PDAC classification based on immunologic parameters. This consensus clustering approach indicated transcriptomic signatures based on immune infiltrate classified as adaptive, innate and immune‐exclusion subtypes. This reveals the existence of microenvironmental interpatient heterogeneity within PDAC and could serve to drive novel therapeutic strategies in PDAC including immune modulation approaches to treating this disease.

Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation

“…Importantly, we have verified the correlation between TP63 and IL1A expression in three independent transcriptome studies of human PDA tumors. In addition, a recent transcriptome study of human tissue samples revealed a correlation between squamous subtype PDA tumors and inflammation-associated changes in the stroma, which validates that our observations in experimental models are in accord with clinical observations (de Santiago et al, 2019). While the aberrant expression of TP63 confers a myriad of tumor cell-intrinsic phenotypes in PDA, such as enhanced motility, invasion, and resistance to cytotoxic chemotherapy (Danilov et al, 2011;Somerville et al, 2018), our work points to a powerful non cell-autonomous effect of TP63 in PDA in promoting inflammation.…”

Nerve Fibers in the Tumor Microenvironment Are Co-Localized with Lymphoid Aggregates in Pancreatic Cancer

“…To further understand to what extent immune cells and nerve fibers may interact, each routine H&E slide was scored manually into a lymphocyte-predominant, neutrophil-predominant or immune-cell-depleted phenotype [ 22 ]. The scoring was done by a senior pathologist and the Ph.D. and based on the most dominant immune cell on one tumor slide only by viewing the histology on HE staining.…”

Activated regulatory T-cells, dysfunctional and senescent T-cells dominate the microenvironment of pancreatic cancer

“…The CD8 + T-cells were defined as the remaining clusters which co-express CD8A and CD8B . The following filters were used for cluster definitions of validated cell populations: Tregs (positive expression of FOXP3 ); Senescent (negative expression of CD27 and CD28 , positive 75 th percentile expression of KLRG1 and positive mean expression of B3GAT1 ); Exhausted (positive 75 th quantile expression of ≥ 4 of HAVCR2, PDCD1, TOX, LAG3, CTLA4, TIGIT, CD38, ENTPD-1 and positive expression of TRDC was filtered out to exclude gamma-delta T-cells).…”

“…Early diagnosis with surgical resection followed by combination chemotherapy offers the best chance of long-term survival (2). We and others have shown that the immune infiltrate in the primary pancreatic tumour is prognostic of the clinical course after a surgical resection (3,4).…”

“…Pancreatic cancer has a complex immune microenvironment with T-cells, macrophages, neutrophils, NK cells, B-cells and dendritic cells present (5)(6)(7)(8)(9).…”