Autophagy-Mediated Exosomes as Immunomodulators of Natural Killer Cells in Pancreatic Cancer Microenvironment

Abstract

Pancreas ductal adenocarcinoma is a highly aggressive cancer with an incredible poor lifespan. Different chemotherapeutic agents' schemes have been tested along the years without significant success. Furthermore, immunotherapy also fails to cope with the disease, even in combination with other standard approaches. Autophagy stands out as a chemoresistance mechanism and is also becoming relevant as responsible for the inefficacy of immunotherapy. In this complex scenario, exosomes have emerged as a new key player in tumor environment. Exosomes act as messengers among tumor cells, including tumor microenvironment immune cells. For instance, tumor-derived exosomes are capable of generating a tolerogenic microenvironment, which in turns conditions the immune system behavior. But also, immune cells-derived exosomes, under non-tolerogenic conditions, induce tumor suppression, although they are able to promote chemoresistance. In that way, NK cells are well known key regulators of carcinogenesis and the inhibition of their function is detrimental for tumor suppression. Additionally, increasing evidence suggests a crosstalk between exosome biogenesis and the autophagy pathway. This mini review has the intention to summarize the available data in the complex relationships between the autophagy pathway and the broad spectrum of exosomes subpopulations in pancreatic cancer, with focus on the NK cells response.

Keywords: autophagy; exosomes; natural killer cells; pancreatic cancer; tumor microenvironment.

Figure 1

Schematic diagram depicting a proposal model of the complex relationship between autophagy and exosomes in the context of pancreas ductal adenocarcinoma (PDAC) and its environment. The autophagy pathway and exosomes biogenesis are suggested to be highly interconnected. Both pathways share several structures of the endo-lysosomal system. In the context of PDAC and its tumor microenvironment, autophagy and exosomal processes are mutually influenced and condition tumor behavior responding to the pressure of the immune system. (1) – violet arrows - Cancer-associated fibroblasts (CAFs) foster proliferation and chemoresistance. Exosomes bearing miR-106b are released by gemcitabine-treated CAFs increasing proliferation and survival of PDAC cell lines. The effector response is traduced in cancer cells as induction of chemoresistance-inducing factors, Snail, and miR-146a, and TP53INP1. (2) – light blue arrows - Bone marrow mesenchymal stem cell (BMSC)-derived exosomes contain miR-126-3p and miR-1231, which in turn inhibit proliferation, invasion and metastasis and promotes apoptosis by down-regulation of disintegrin and metalloproteinase-9 (ADAM9). (3) – brown arrows - Vesicles from tumor-associated stroma cells (TASC) are enriched in miR-145. This molecule possesses tumor suppressor action on target cells by inducing apoptosis. (4) – green arrows - NK-derived exosomes mediate tumor cells suppression by two mechanisms. One of them is Fas-FasL interaction between exosomes and tumoral cells. The other mechanism is mediated by excessive uptake by cancer cells of exosomes carrying miR-3607-3p which possess tumor suppressive qualities and decrease IL-26 expression. (5) – purple arrows – PDAC tumor exosomes (TEXs) bearing c-Met and PD-L1 enhance carcinogenesis. c-Met provides proliferation, migration, and an anti-apoptotic status in recipient cancer cells. PD-L1 guarantees evasion of immune control. (6) – black arrow – TEXs from highly invasive cells carry ZIP4, miR-125b-5p and miR-5703 towards weakly invasive cancer cells enhancing the aggressiveness of these last and promoting an increased invasive potential. (7) – orange arrows – In response to gemcitabine treatment, chemoresistant PDAC cancer cells are capable of transferring their resistance properties to neighboring cells through exosomes. They release TEXs bearing miR-155 and induce upregulation of SOD2 and CAT meanwhile DCK, a gene related to gemcitabine metabolism, is downregulated. Furthermore, exosomes from different cell types of tumor microenvironment condition autophagy response and affect PDAC behavior. EE, Early endosomes; LE/MVB, Late Endosomes/Multivesicular bodies; ER, endoplasmic reticulum; TEX, Tumor-derived exosomes.