Macrophage regulation of B cell proliferation

Goldman, Naomi; Valiuskyte, Kornelija; Londregan, Jennifer; Swider, Adam; Somerville, John; Riggs, James E.

doi:10.1016/j.cellimm.2017.02.002

Cited by 14 publications

(12 citation statements)

References 63 publications

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“…PerC cell culture provides a simple, in vitro model of the Mϕ-rich tumor microenvironment (TME) wherein lymphocyte expansion is tempered by mechanisms that vary depending upon cell culture density, form of lymphocyte activation, and mouse strain [16–18]. Unlike spleen (SP) cells, which have low macrophage composition and respond to antigen receptor (TCR/anti-CD3) ligation, C57BL/6J PerC cells failed to incorporate tritiated thymidine unless IFNγ was neutralized or iNOS was inhibited by 1-MA (Figure 1A, B).…”

Section: Resultsmentioning

confidence: 99%

“…In culture, these cells aggregate to reproduce key features of the TME. We have shown how the shape of the tissue culture well (“V”, “U”, or flat bottom) and cell concentration alter normal lymphocyte biology [16–18]. Essentially, conditions that increase IFNγ production, e.g., costimulation by CD28 ligation, increase T cell suppression by increasing iNOS production [17].…”

Section: Discussionmentioning

confidence: 99%

“…We model the TME by studying Mϕ-rich peritoneal cavity (PerC) cells in vitro and have reported on how Mϕs suppress PerC B and T cell proliferation following B/TCR ligation [15–18]. IFNγ is essential for suppression of PerC T cells and is a key driver of inhibitory PD-L1 expression [17–19].…”

Section: Introductionmentioning

confidence: 99%

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High macrophage PD-L1 expression not responsible for T cell suppression

Goldman

Lomakova

Londregan

et al. 2018

Cellular Immunology

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Tumors are often comprised of microenvironments (TMEs) with a high proportion of cells and molecules that regulate immunity. Peritoneal cavity (PerC) cell culture reproduces key features of TMEs as lymphocyte proliferation is suppressed by PerC macrophages (Mϕs). We monitored the expression of T cell stimulatory (Class II MHC, B7) and inhibitory (PD-L1) molecules by PerC APCs before and after culture and report here that IFNγ-driven PD-L1 expression increased markedly on PerC Mϕs after TCR ligation, even more so than seen with direct APC activation by LPS. Considering the high APC composition of and pronounced PD-L1 expression by PerC cells, it was surprising that blocking PD-1/PD-L1 interaction by mAb neutralization or genetic ablation did not relieve suppression. This result parallels TME challenges observed in the clinic and validates the need for further study of this culture model to inform strategies to promote anti-tumor immunity.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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High macrophage PD-L1 expression not responsible for T cell suppression

Goldman

Lomakova

Londregan

et al. 2018

Cellular Immunology

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“…However, additional soluble factors present in the peritoneal cavity, including IL-10 produced by B-1 cells and macrophage-produced prostaglandins, indoleamine 2,3-dioxygenase, and nitric oxide drive immunosuppression(11–15). Under normal conditions, both peritoneal B-1 cells and macrophages inhibit T cell activation and peritoneal macrophages additionally inhibit B cell proliferation and antibody production (11–13,15,16). Ascites from carcinomatosis patients contains high levels of IL-10, TGF-β, regulatory T cells, and immunosuppressive macrophages (17), suggesting suppression within the peritoneal cavity is maintained, if not augmented, in peritoneal metastases.…”

Section: Introductionmentioning

confidence: 99%

Activation of B-1 Cells Promotes Tumor Cell Killing in the Peritoneal Cavity

et al. 2019

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Metastatic cancer involving spread to the peritoneal cavity is referred to as peritoneal carcinomatosis and has a very poor prognosis. Activating the anti-tumor immune response in the characteristically immune-suppressive peritoneal environment presents a potential strategy to treat this disease. In this study, we show that a toll-like receptor (TLR) and C-type lectin receptor (CLR) agonist pairing of monophosphoryl lipid A (MPL) and trehalose-6,6'-dicorynomycolate (TDCM) effectively inhibits tumor growth and ascites development in a mouse model of aggressive mammary cancer-induced peritoneal carcinomatosis. MPL/TDCM treatment similarly inhibited peritoneal EL4 tumor growth and ascites development. These effects were not observed in mice lacking B cells or mice lacking CD19, which are deficient in B-1a cells, an innate-like B cell population enriched in the peritoneal cavity. Remarkably, adoptive transfer of B-1a cells, but not splenic B cells from WT mice restored MPL/TDCM-induced protection in mice with B cell defects. Treatment induced B-1 cells to rapidly produce high levels of natural IgM reactive against tumor-associated carbohydrate antigens. Consistent with this, we found significant deposition of IgM and C3 on peritoneal tumor cells as early as 5 days post-treatment. Mice unable to secrete IgM or complement component C4 were not protected by MPL/TDCM treatment, indicating tumor killing was mediated by activation of the classical complement pathway. Collectively, our findings reveal an unsuspected role for B-1 cell-produced natural IgM in providing protection against tumor growth in the peritoneal cavity, thereby highlighting potential opportunities to develop novel therapeutic strategies for the prevention and treatment of peritoneal metastases.

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“…Distinct from organized lymphoid tissue, the peritoneum harbors an immune cell composition marked by a large fraction of CD11b hi F4/80 + Mϕs, as well as activated (CD44 hi ) T and B cell subsets 9 . The increased proportional representation of Mϕs is essential for the immune suppression observed in PerC cell culture 9–12 . Following TCR ligation, PerC T cells produce IFNγ, which triggers Mϕ iNOS expression 9–11 .…”

Section: Introductionmentioning

confidence: 99%

PHA eludes macrophage suppression to activate CD8+ T cells

et al. 2019

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Tumors may include a high proportion of immune modulatory cells and molecules that restrain the anti-cancer response. Activation of T cells to eliminate cancer cells within the immune-suppressive tumor microenvironment remains a challenge. We have shown that C57BL/6J peritoneal cell culture models features of macrophage-dense tumors as TCR ligation fails to activate T cells unless IFNγ is neutralized or iNOS is inhibited. We tested other forms of T cell activation and found phytohemagglutinin (PHA) distinctive in the ability to markedly expand CD8 T cells in this model. IFNγ or iNOS inhibition was not necessary for this response. PHA triggered less IFNγ production and inhibitory PD-L1 expression than TCR ligation. Macrophages and CD44hi T cells bound PHA. Spleen T cell responses to PHA were markedly enhanced by the addition of peritoneal cells revealing that macrophages enhance T cell expansion. That PHA increases CD8 T cell responses within macrophage-dense culture suggests this mitogen might enhance anti-tumor immunity.

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Macrophage regulation of B cell proliferation

Cited by 14 publications

References 63 publications

High macrophage PD-L1 expression not responsible for T cell suppression

High macrophage PD-L1 expression not responsible for T cell suppression

Activation of B-1 Cells Promotes Tumor Cell Killing in the Peritoneal Cavity

PHA eludes macrophage suppression to activate CD8+ T cells

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