Tumour microenvironment of pancreatic cancer: immune landscape is dictated by molecular and histopathological features

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Abstract

Pancreatic cancer is a lethal disease, with fewer than 7% of patients surviving beyond 5 years following diagnosis. Immune responses are known to influence tumour progression. The dynamic interaction between cancer cells and immune cells in the tumour microenvironment (TME) can not only result in, or be influenced by, different tumour characteristics, but it can also lead to diverse mechanisms of immune evasion. At present, there is much interest in classifying pancreatic cancer according to its morphologic, genetic and immunologic features in order to understand the significant heterogeneity of this tumour type. Such information can contribute to the identification of highly needed novel prognostic and predictive biomarkers, and can be used for accurate patient stratification and therapy guidance. This review focuses on the characteristics of the local immune contexture of pancreatic ductal adenocarcinoma and the interaction between tumour cells and immune cells within the TME, by simultaneously taking into account the histomorphologic and genetic features of the tumours. The emerging opportunities for approaches that could predict the most-effective therapeutic modalities towards more targeted, personalised treatments to improve patient care are also discussed.

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Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma

Richard A Moffitt, Raoud Marayati, Elizabeth Flate … (2015)

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with a 5-year survival of 4%. A key hallmark of PDAC is extensive stromal involvement, which makes capturing precise tumor-specific molecular information difficult. Here, we have overcome this problem by applying blind source separation to a diverse collection of PDAC gene expression microarray data, which includes primary, metastatic, and normal samples. By digitally separating tumor, stroma, and normal gene expression, we have identified and validated two tumor-specific subtypes including a “basal-like” subtype which has worse outcome, and is molecularly similar to basal tumors in bladder and breast cancer. Furthermore, we define “normal” and “activated” stromal subtypes which are independently prognostic. Our results provide new insight into the molecular composition of PDAC which may be used to tailor therapies or provide decision support in a clinical setting where the choice and timing of therapies is critical.

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Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma

(2017)

We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine.

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John Neoptolemos, Daniel H Palmer, Paula Ghaneh … (2017)

The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer.