Replies to post #322563 on Avid Bioservices Inc (CDMO)

[jbainseky]

Thanks for the find Hutschi,

Mmmmm yea, nothing there....

Externalization of PS Stimulates Immune-Suppressive Mechanisms

Under non-stress conditions, PS is selectively found on the inner leaflet of plasma membranes. Following environmental stress or in aging cells PS gets externalized to the outer membrane leaflet by scramblases. Externalized PS on dying normal cells acts as a dominant, anti-inflammatory eat-me signal for phagocytosis (efferocytosis) that allows controlled apoptotic cell death (30). Pathologically, the immunosuppressive activity of externalized PS has been converted into pro-inflammatory signals that can also support tumor progression. Upon hypoxic stress, the localization of PS is severely dysregulated in tumor and stromal cells (infiltrating MDSCs within the tumor stroma included) (30). If the controlled apoptotic clearance of tumor cells fails, secondary necrosis can be initiated which in turn can induce chronic inflammation and autoimmunity (31). A rapid removal of PS exposing apoptotic by phagocytosis is pivotal to prevent inflammatory responses and the maintenance of tolerogenic signals during homeostasis which in turn can downregulate antitumor immune responses. Furthermore, binding of PS exposing tumor-derived exosomes to PS-receptors (e.g., TIM-receptors on immune cells) (32), can also induce evolutionary conserved immune-suppressive signals (enhanced TGF-ß and interleukin-10 secretion) that can further inactivate antitumor immune responses.

Conclusion

From the data presented, it is evident that hypoxia-/HIF-1a-driven features of the TME, such as ADO and lactate accumulation, extracellular acidosis, VEGF overexpression, and VEGF-R activation, and PS-externalization from the inner to the outer leaflet of tumor cells or tumor-derived exosomes are accomplices (“fatal sextet” of TME) sabotaging spontaneous and therapeutically induced antitumor immune responses. Therapeutic strategies counteracting the immune-suppressive activities of these adverse factors have been reviewed recently (14, 15).

FFTT

JBAIN