336 - Molecular mechanisms involved in the immunomodulation induced by LIF in cancer

Abstract

LIF is a pleiotropic cytokine that can act as an immunomodulatory factor in different biological processes, such as embryo implantation, organ transplantation tolerance and multiple sclerosis. Here, we have observed that in tumors expressing LIF, its blockade inhibits tumor growth, and that the anti-tumor effect of LIF neutralization is mediated by the polarization of tumor-associated myeloid cells (TAMCs). LIF sustains the expression of CCL22, MRC1 and CD163 in human healthy monocytes and in TAMCs from mouse syngeneic (non-small cell lung cancer, ovarian cancer and colorectal cancer) models, patient-derived xenograft models and organotypic cultures from glioblastoma. We show that LIF blockade down-regulates CCL22 secretion by TAMCs preventing regulatory T cell and inducing effector T and NK cell tumor infiltration, leading to an increase in tumor cell apoptosis and an anti-tumor response. A positive correlation between M2-like markers and LIF expression has been observed in glioblastoma patients, and high levels of these factors confer poor prognosis. Moreover, we have studied one of the multiple mechanisms through which LIF could modulate the inhibition of effector T and NK cells: the regulation of PD-1/PDL1 axis. We have seen that after anti-LIF treatment of tumor-bearing mice, the expression of PDL1 decreases in tumor cells and in TAMCs. Furthermore, a positive correlation between PDL1 and LIF expression has been observed in glioblastoma patients, and both proteins also correlate with CD44 expression, a marker for cancer-initiating cell (CIC) population. High levels of these three factors confer poor prognosis. Thus, we have found that LIF acts as an immune-suppressor in cancer recapitulating its normal function in other biological processes. LIF is a bridge between the innate and adaptive immune responses through the induction of CCL22 in TAMCs and subsequent regulation of regulatory and effector T and NK cells. Our results identify LIF as a promising immuno-oncology therapeutic target and establish the translational potential of anti-LIF agents.