Immune checkpoint regulator PD-L1 expression on tumor cells by contacting CD11b positive bone marrow derived stromal cells

Noh, Hyangsoon; Hu, Jiemiao; Wang, Xiaohong; Xia, Xueqing; Satelli, Arun; Li, Shulin

doi:10.1186/s12964-015-0093-y

Cited by 46 publications

(45 citation statements)

References 41 publications

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“…In addition, enzalutamide exposure alone leads to upregulation of Snail and PD-L1 (Bishop et al, 2015), and our data demonstrates Snail activation can upregulate PD-L1 expression. Consistent with this, PD-L1 is upregulated on melanoma cells through activation of p38 (Noh et al, 2015), providing further strong support for our hypothesis that the p38/Snail axis drives PD-L1 expression. Similarly, in both chronic viral infections and cancer, p38 activation has been linked to inhibition of Stimulator of IFN genes (STING) expression, enhanced CXCR2-mediated myeloid derived suppressor cell activity, and immune evasion (Chen et al, 2017; Wang et al, 2006; Zhang et al, 2017).…”

Section: Discussionsupporting

confidence: 83%

Convergent evolution of p38/MAPK activation in hormone resistant prostate cancer mediates pro-survival, immune evasive, and metastatic phenotypes

Ware

Gupta

Eng

et al. 2020

Preprint

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SummaryAdaptation of cancer cells to targeted therapy follows ecological paradigms observed in natural populations that encounter resource depletion and changing environments, including activation of pro-survival mechanisms, migration to new locations, and escape of predation. We identified the p38 MAPK pathway as a common molecular driver of these three responses during the adaptation to hormone therapy resistance in prostate cancer. The p38 pathway is activated in therapy-resistant cells and mechanistically drives these three convergent responses through sustained AR activity, enhanced invasion and metastasis, and immune evasion. Targeting p38 signaling may represent a new therapeutic strategy to treat men with metastatic, hormone therapy-resistant prostate cancer.

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Section: Discussionsupporting

confidence: 83%

Convergent evolution of p38/MAPK activation in hormone resistant prostate cancer mediates pro-survival, immune evasive, and metastatic phenotypes

Ware

Gupta

Eng

et al. 2020

Preprint

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“…It was also reported previously that bone marrow-derived macrophages could trigger upregulated PD-L1 expression by tumor cells upon physical contact, in a mechanism that that was reported to be dependent on contact between macrophage CD11b and tumor cells [39]. However, the results of this prior study could also be explained by tumor-induced secretion of macrophage TNF-α, since their studies did not examine the effects of CM from the co-cultures on tumor PD-L1 expression.…”

Section: Discussionmentioning

confidence: 69%

Regulation of PD-L1 expression on murine tumor-associated monocytes and macrophages by locally produced TNF-α

Hartley

Regan

Guth

et al. 2017

Cancer Immunol Immunother

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PD-L1 is an immune checkpoint protein that has emerged as a major signaling molecule involved with tumor escape from T cell immune responses. Studies have shown that intra-tumoral expression of PD-L1 can inhibit antitumor immune responses. However, it has recently been shown that expression of PD-L1 on myeloid cells from the tumor is a stronger indicator of prognosis than tumor cell PD-L1 expression. Therefore, it is important to understand the factors that govern the regulation of PD-L1 expression on tumor-infiltrating myeloid cells. We found that immature bone marrow monocytes in tumor-bearing mice had low levels of PD-L1 expression, while higher levels of expression were observed on monocytes in circulation. In contrast, macrophages found in tumor tissues expressed much higher levels of PD-L1 than circulating monocytes, implying upregulation by the tumor microenvironment. We demonstrated that tumor-conditioned media strongly induced increased PD-L1 expression by bone marrow-derived monocytes and TNF-α to be a cytokine that causes an upregulation of PD-L1 expression by the monocytes. Furthermore, we found production of TNF-α by the monocytes themselves to be a TLR2-dependent response to versican secreted by tumor cells. Thus, PD-L1 expression by tumor macrophages appears to be regulated in a different manner than by tumor cells themselves.

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“…To reveal IL‐6 downstream signaling pathways that are responsible for the IL‐6‐mediated upregulation of PD‐L1/downregulation of NKG2D ligands in CRPC cells, we analyzed the expression/activation of molecules that have been previously reported to be involved in PD‐L1 regulation in C4‐2siIL‐6/sc and CWRsiIL‐6/sc cells. These included JAK1/2 (Bellucci et al ., ; Ikeda et al ., ), Stat3 (Fujita et al ., ; Marzec et al ., ), Akt‐mTOR (Lastwika et al ., ), NFκB (Gowrishankar et al ., ), mitogen‐activated protein kinase/ERK kinase (MEK), extracellular signal‐regulated kinase (ERK) (Yamamoto et al ., ), PI3K/Akt (Xu et al ., ), and MAPK (Noh et al ., ) pathways. We found many signaling pathways, including JAKs, Stat3, MAPK, MEK, Erk, were activated in IL‐6‐expressing cells compared to IL‐6‐knockdown cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of IL‐6‐JAK/Stat3 signaling in castration‐resistant prostate cancer cells enhances the NK cell‐mediated cytotoxicity via alteration of PD‐L1/NKG2D ligand levels

Chen

Shen

et al. 2018

Molecular Oncology

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To investigate whether IL‐6 signaling affects the susceptibility of castration‐resistant prostate cancer (CRPC) cells to cytotoxic action of natural killer (NK) cells, CRPC cell lines (having different IL‐6 levels) were developed by lentiviral transduction. While observing no secreted IL‐6 level in parental C4‐2 and CWR22Rv1 cells, we found the IL‐6 expression/secretion in these cells was induced after the transduction process and the IL‐6 level difference in C4‐2siIL‐6/sc and CWR22siIL‐6/sc cell CRPC cell sets could be detected. We then found that IL‐6‐knockdown cells were more susceptible to NK cell cytotoxicity than control cells due to lowered programmed death receptor ligand 1 (PD‐L1) and increased NK group 2D (NKG2D) ligand levels. In animal studies, to concur with the in vitro results, we found that IL‐6‐expressing cell‐derived tumors were more resistant to NK cell action than the tumors of IL‐6‐knockdown cells. Further, we discovered that JAK‐Stat3 is the most critical IL‐6 downstream signaling that modulates PD‐L1/NKG2D ligand levels in CRPC cells. Furthermore, inhibition of the JAK or Stat3 signaling effectively increased the susceptibility of C4‐2sc and CWRsc cells to NK cell cytotoxicity. We observed the most effective cytotoxicity when the PD‐L1 Ab and JAK inhibitor (or Stat 3 inhibitor) were used together. These results suggest that the strategy of targeting IL‐6 signaling (or its downstream signaling) may enhance the NK cell‐mediated immune action to CRPC tumors, thus yielding clinical implications in developing future immunotherapeutics of exploiting this strategy to treat patients with CRPC.

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Immune checkpoint regulator PD-L1 expression on tumor cells by contacting CD11b positive bone marrow derived stromal cells

Cited by 46 publications

References 41 publications

Convergent evolution of p38/MAPK activation in hormone resistant prostate cancer mediates pro-survival, immune evasive, and metastatic phenotypes

Convergent evolution of p38/MAPK activation in hormone resistant prostate cancer mediates pro-survival, immune evasive, and metastatic phenotypes

Regulation of PD-L1 expression on murine tumor-associated monocytes and macrophages by locally produced TNF-α

Inhibition of IL‐6‐JAK/Stat3 signaling in castration‐resistant prostate cancer cells enhances the NK cell‐mediated cytotoxicity via alteration of PD‐L1/NKG2D ligand levels

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