Tumor stroma-derived factors skew monocyte to dendritic cell differentiation toward a suppressive CD14⁺PD-L1⁺phenotype in prostate cancer

Abstract

Tumor-associated stromal myofibroblasts are essential for the progression and metastatic spread of solid tumors. Corresponding myeloid cell infiltration into primary tumors is a negative prognostic factor in some malignancies. The aim of this study was to define the exact role of stromal myofibroblasts and stromal factors in early prostate carcinoma (PCa) regulating monocyte infiltration and differentiation into dendritic cells (DCs). Epithelial and stromal primary cultures were generated from PCa biopsies and their purity confirmed. Stromal cells produced significantly more of the (C-C) motif chemokine ligand 2 (CCL2), interleukin 6 (IL-6) and transforming growth factor β (TGFβ) than epithelial cells. Monocyte chemoattraction was predominantly due to stromal-derived factors, mainly CCL2. DCs generated in the presence of stromal (but not epithelial) factors upregulated CD209, but failed to downregulate the monocyte marker CD14 in a signal transducer and activator of transcription 3 (STAT3)-dependent manner. Monocytes exposed to stromal factors did not produce detectable amounts of IL-10, however, upon lipopolysaccharide stimulation, stromal factor generated dendritic cells (sDC) produced significantly more IL-10 and less IL-12 than their conventional DC counterparts. sDC failed to cross-present tumor-antigen to CD8 T cells and suppressed T-cell proliferation. Most importantly, sDC expressed significantly elevated levels of programmed cell death ligand-1 (PD-L1) in a primarily STAT3 and IL-6-dependent manner. In parallel with our findings , tumor-infiltrating CD14 cells were found to express both PD-L1 and CD209, and a higher percentage of tumor-associated CD3 T cells expressed programmed cell death-1 (PD-1) molecules compared to T cells in blood. These results demonstrate a hitherto undescribed, fundamental contribution of tumor-associated stromal myofibroblasts to the development of an immunosuppressive microenvironment in early PCa.

CCL15 Recruits Suppressive Monocytes to Facilitate Immune Escape and Disease Progression in Hepatocellular Carcinoma

“…Therefore, it appeared that the types of CCR1 + cells were diverse in different tumor microenvironments. Mechanistically, aberrant expression of PD‐L1 was reported to reprogram monocytes toward the immune‐suppressive direction . In this study we showed that, in addition to immune checkpoint, upregulation of immune tolerogenic metabolic enzymes, inflammatory/pro‐antigenic cytokines and matrix remodeling proteases, as well as inflammatory chemokines, may collectively foster the pro‐tumor function of HCC‐infiltrating CCR1 + CD14 + monocytes.…”

Prostaglandin E2-mediated adenosinergic effects on CD14+cells: Self-amplifying immunosuppression in cancer

“…In order to explore the consequences of STAT3 activation, we inhibited STAT3 phosphorylation with the small molecule inhibitor Cpd188 in cells exposed to sPE, at a concentration we have established previously. 29 Unexpectedly, in the presence of the inhibitor, sPEmediated induction of CD73 expression became significantly enhanced (Fig. 4B).…”

STAT3 inhibition for cancer therapy: Cell-autonomous effects only?

“…25 Notably, the expression of CD274 (a potent immunosuppressive molecule also known as PD-L1) by MDSCs and other immunosuppressive myeloid cells also depends on STAT3. 26 This latter observation suggests that STAT3 inhibition may downregulate PD-L1, implying that combining AZD9150 with checkpoint blockers 27,28 targeting the interaction between PD-L1 and its main receptor (programmed cell death 1, PDCD1, best known as PD-1) may not be useful. However, this conjecture remains to be investigated at the experimental level.…”