Tumour plasticity and tumour microenvironment interactions as potential immunologic targets for pancreatic cancer treatment.

Pancreatic ductal adenocarcinoma (PDAC) is a malignant cancer with a high mortality and limited treatment options. Systemic chemotherapy remains the only approach for improving survival in patients with unresectable locally advanced and/or metastatic disease which comprises most patients. Targeted therapies have so far been disappointing with limited applicability and improvement in overall survival. Patients with resectable PDAC have improved survival with adjuvant chemotherapy, whereas neoadjuvant chemotherapy is the best option for borderline resectable PDAC. In patients with locally advanced unresectable PDAC, resection rates may be improved with induction chemotherapy and possibly radiotherapy. Immunotherapy has proved to be relatively effective in multiple solid cancer types, and yet has shown poor or no efficacy in PDAC treatment. With the development of tumour and tumour microenvironment (TME) stratification by transcriptomic and histological profiling, we are able to have a deeper understanding of the clinical implications of TME heterogeneity and tumour plasticity. PDAC and stromal cells within the TME including cancer associated fibroblasts can be reprogrammed under certain treatment conditions to switch, at least to some extent, the whole immune-cold complex towards a more immune-hot and chemo-sensitive state. This approach may provide us with a new perspective in the design of immunotherapy and chemotherapy combination regimens.