Phenotypic heterogeneity and tumour immune microenvironment directed therapeutic strategies in pancreatic ductal adenocarcinoma

Remya PG Ramesh ¹ Hadida Yasmin ² Pretty Ponnachan ¹ Uday Kishore ^1* Ann Mary Joseph ¹

• ¹ United Arab Emirates University, Al-Ain, United Arab Emirates
• ² Cooch Behar Panchanan Barma University, Koch Bihār, West Bengal, India

AbstractPancreatic cancer is an aggressive tumour with high metastatic potential which leads to decreased survival rate and resistant to the chemotherapy and immunotherapy. Nearly 90% of pancreatic cancer comprises pancreatic ductal adenocarcinoma (PDAC). About 80% of diagnosis takes place at the advanced metastatic stage when it is non-resectable, which makes different chemotherapy regimens ineffective. There is also a dearth of specific biomarkers for early-stage detection. Advances in next generation sequencing and single cell profiling have identified molecular alterations and signatures that play a role in PDAC progression and subtype plasticity. Most chemotherapy regimens have shown only modest survival benefits, and therefore, translational approaches for immunotherapies and combination therapies are urgently required. In this review, we have examined the immunosuppressive and dense stromal network of tumour immune microenvironment with the various metabolic and transcriptional changes that aggravate the pro-tumourigenic properties in PDAC in terms of phenotypic heterogeneity, plasticity and subtype co-existence. We have also revisited stromal heterogeneity with genetic and epigenetic changes that impact the PDAC development. We also review the PDAC interaction with sequestered cellular and humoral components present in the tumour immune microenvironment that modify the outcome of chemotherapy and radiation therapy. Finally, we discuss different therapeutic interventions targeting the tumor immune microenvironment aimed at better prognosis and improved survival in PDAC.