ITOC2 – 001. Influence of tumour cell – Fibroblast co-culture on monocyte differentiation and tumour growth in pancreatic cancer

Abstract

Pancreatic cancer (PC) remains one of the most lethal and challenging solid tumours to treat and shows a high unmet medical need as patients poorly respond to standard-of-care-therapies. Prominent desmoplastic reactions involving cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) as well as the inflammatory tumour microenvironment (iTME) play a significant role in tumour progression and in its intrinsic resistance to therapy. To identify the role of immune cells and to investigate cell–cell interactions that are responsible for generating an immunosuppressive tumour microenvironment, we established 3D mono and co-culture models with pancreatic cancer cells, CAFs and monocytes. Soluble immune modulators produced by tumour cell – fibroblast co-cultures can impact monocyte differentiation and influence tumour growth. Using the 3D co-culture model, we analysed the influence of monocytes on immune suppression and tumour cell survival. Upon co-culture of tumour cells and fibroblasts with monocytes, an increase in tumour cell proliferation could be observed. Tumour cell – fibroblast co-culture spheroids primarily induced immunosuppressive M2-like macrophage polarisation as well as the survival of poorly differentiated cells termed myeloid-derived-suppressor cells (MDSCs) that lack the expression of M1/M2 macrophage markers. Further experiments are ongoing to characterise this myeloid cell population phenotypically and functionally and the key factors involved in this mechanism. In conclusion, the resulting data will help to identify key players that induce immunosuppression and tumour progression in pancreatic cancer and to reveal novel resistance mechanisms for an improved development of novel immune-therapeutic strategies.