MUC1-C integrates PD-L1 induction with repression of immune effectors in non-small-cell lung cancer.

Immunotherapeutic approaches, particularly programmed death 1/programmed death ligand 1 (PD-1/PD-L1) blockade, have improved the treatment of non-small-cell lung cancer (NSCLC), supporting the premise that evasion of immune destruction is of importance for NSCLC progression. However, the signals responsible for upregulation of PD-L1 in NSCLC cells and whether they are integrated with the regulation of other immune-related genes are not known. Mucin 1 (MUC1) is aberrantly overexpressed in NSCLC, activates the nuclear factor-κB (NF-κB) p65→︀ZEB1 pathway and confers a poor prognosis. The present studies demonstrate that MUC1-C activates PD-L1 expression in NSCLC cells. We show that MUC1-C increases NF-κB p65 occupancy on the CD274/PD-L1 promoter and thereby drives CD274 transcription. Moreover, we demonstrate that MUC1-C-induced activation of NF-κB→︀ZEB1 signaling represses the TLR9 (toll-like receptor 9), IFNG, MCP-1 (monocyte chemoattractant protein-1) and GM-CSF genes, and that this signature is associated with decreases in overall survival. In concert with these results, targeting MUC1-C in NSCLC tumors suppresses PD-L1 and induces these effectors of innate and adaptive immunity. These findings support a previously unrecognized central role for MUC1-C in integrating PD-L1 activation with suppression of immune effectors and poor clinical outcome.

In vivo induction of myeloid suppressor cells and CD4(+)Foxp3(+) T regulatory cells prolongs skin allograft survival in mice.

Natural CD4(+)Foxp3(+) T regulatory (Treg) cells can promote transplantation acceptance across major histocompatibility complex (MHC) barriers, while myeloid-derived suppressor cells (MDSCs) inhibit effector T-cell responses in tumor-bearing mice. One outstanding issue is whether combining the potent suppressive function of MDSCs with that of Treg cells might synergistically favor graft tolerance. In the present study, we evaluated the therapeutic potential of MDSCs and natural Treg cells in promoting allograft tolerance in mice by utilizing immunomodulatory agents to expand these cells in vivo. Upon administration of recombinant human granulocyte-colony stimulating factor (G-CSF; Neupogen), or interleukin-2 complex (IL-2C), Gr-1(+)CD11b(+) MDSCs or CD4(+)Foxp3(+) Treg cells were respectively induced at a high frequency in the peripheral lymphoid compartments of treated mice. Interestingly, induced MDSCs exhibited a more potent suppressive function in vitro when compared to MDSCs from naive mice. Furthermore, in vivo coadministration of Neupogen and IL-2C induced MDSCs at percentages that were higher than those seen when either agent was administered alone, suggesting an additive effect of the two drugs. Although treatment with either IL-2C or Neupogen led to a significant delay of MHC class II disparate allogeneic donor skin rejection, the combinatorial treatment was superior to either alone. Importantly, histological assessment of surviving grafts revealed intact morphology and minimal infiltrates at 60 days posttransplant. Collectively, our findings demonstrate that concurrent induction of MDSCs and Tregs is efficacious in downmodulating alloreactive T-cell responses in a synergistic manner and highlight the therapeutic potential of these naturally occurring suppressive leukocytes to promote transplantation tolerance.