PD-1 Suppresses Development of Humoral Responses That Protect against Tn-Bearing Tumors

Haro, Marcela; Littrell, Chad A.; Yin, Zhaojun; Huang, Xuefei; Haas, Karen M.

doi:10.1158/2326-6066.cir-16-0184

Cited by 20 publications

(30 citation statements)

References 45 publications

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“…10 4 TA3-Ha cells injected i.p. into naïve WT C57BL/6 mice induces visible ascites between days 8–10 with mice rapidly succumbing to tumor growth and ascites development (22), similar to CAF 1 and A/J mice (Fig. 2A).…”

Section: Resultsmentioning

confidence: 76%

“…Cells were washed and stained with streptavidin-conjugated fluorochrome for 20 minutes, washed and fixed with 1.5% buffered formaldehyde. TA3-Ha cells were identified as HPA + CD11b neg CD138 + MHC-I + CD19 - (22). To detect Ig and C3 bound to tumor cells harvested from peritoneal cavities, cells were incubated with Fc Block for 15 minutes prior to addition of biotinylated HPA (2.5 μg/ml) and mAbs against CD138, MHC class I, CD19, CD11b, and goat anti-mouse Ig (H+L) (Invitrogen) and anti-mouse C3 IgG–FITC (Cappel).…”

Section: Methodsmentioning

confidence: 99%

“…Isotype controls were used to define positive and negative populations. Serum IgM and IgG binding (1:10 dilution) to tumor cells was assessed as previously described (22). Bovine submaxillary mucin (MP Biologicals) was included as a blocking agent (100 μg/ml) in some experiments.…”

Section: Methodsmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 76%

Section: Methodsmentioning

confidence: 99%

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

et al. 2019

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“…B cell-expressed PD-1 plays a major role in suppressing Ab production to pneumococcal polysaccharide, as well as other T cell– independent type 2 antigens (TI-2 Ags) and tumor-associated carbohydrate Ags (48–50). Evidence supports that PD-1 specifically induced on Ag-specific B-1b cells suppresses B cell proliferation and differentiation to IgG-producing cells (48).…”

Section: Introductionmentioning

confidence: 99%

PD-L2 Regulates B-1 Cell Antibody Production against Phosphorylcholine through an IL-5–Dependent Mechanism

McKay

Haro

Daly

et al. 2017

The Journal of Immunology

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B-1 cells produce natural antibodies which provide an integral first line of defense against pathogens while also performing important homeostatic housekeeping functions. In this study, we demonstrate programmed cell death 1 ligand 2 (PD-L2) regulates the production of natural antibodies against phosphorylcholine (PC). Naïve PD-L2-deficient (PD-L2−/−) mice produced significantly more PC-reactive IgM and IgA. This afforded PD-L2−/− mice with selectively enhanced protection against PC-expressing non-typeable Haemophilus influenzae (NTHi), but not PC-negative NTHi, relative to wild type mice. PD-L2−/− mice had significantly increased PC-specific CD138+ splenic plasmablasts bearing a B-1a phenotype, and produced PC-reactive Abs largely of the T15 idiotype. Importantly, PC-reactive B-1 cells expressed PD-L2 and irradiated chimeras demonstrated B cell-intrinsic PD-L2 expression regulated PC-specific Ab production. In addition to increased PC-specific IgM, naïve PD-L2−/− mice and irradiated chimeras reconstituted with PD-L2−/− B cells had significantly higher levels of IL-5 – a potent stimulator of B-1 cell Ab production. PDL2 mAb blockade of wild type B-1 cells in culture significantly increased CD138 and Blimp1 expression and PC-specific IgM, but did not affect proliferation. PDL2 mAb blockade significantly increased IL-5+ T cells in culture. Both IL-5 neutralization and STAT5 inhibition blunted the effects of PDL2 mAb blockade on B-1 cells. Thus, B-1 cell-intrinsic PD-L2 expression inhibits IL-5 production by T cells and thereby limits natural Ab production by B-1 cells. These findings have broad implications for the development of therapeutic strategies aimed at altering natural Ab levels critical for protection against infectious disease, autoimmunity, allergy, cancer, and atherosclerosis.

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“…This model has been used in investigations of Tn-based cancer vaccines in vivo (Lo-Man et al, 2001, 2004). TA3Ha cells are derived from A/J mouse strain (Thingstad & Hilkens, 2003), but can grow well in both C57BL/6 and BALB/c mice (Leyva, Littrell, Yin, Huang, & Haas, 2016; Lo-Man et al, 2001; Yin et al, 2015). To mimic clinical condition for tumor therapy, vaccination is performed after mice receive injection of tumor cells.…”

Section: Vaccination With Qβ-tn Can Protect Mice From Death Due Tomentioning

confidence: 99%

Evaluation of Virus-Like Particle-Based Tumor-Associated Carbohydrate Immunogen in a Mouse Tumor Model

Sungsuwan

Huang

2017

Methods in Enzymology

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Tumor-associated carbohydrate antigens (TACAs) are attractive targets for anticancer vaccine development. Due to the low immunogenicity of TACAs, a powerful carrier system is needed to boost immune responses. Virus-like particles (VLPs) are an exciting platform for delivering TACAs to the immune system. The high symmetry of VLPs enables the display of TACAs in an organized manner, which in turn can potently activate antibody secreting B cells, eliciting high titers of antiglycan IgG antibodies. In this chapter, the protocol for conjugating a prototypical TACA, the Tn antigen to a VLP, bacteriophage Qβ, is presented. On an average around 370 copies of Tn can be attached to each Qβ capsid. Immunization of mice with Qβ-Tn conjugate leads to over two orders of magnitude higher IgG antibodies compared to control mice receiving Qβ only without the Tn antigen. Antibodies induced by Qβ-Tn recognize Tn-expressing tumor cells strongly and protect mice from tumor-induced death. The techniques for evaluating antibody titers by enzyme-linked immunosorbent assay, antibody binding to tumor cells by flow cytometry, and the protection efficacy of the vaccine in a therapeutic model of tumor are discussed in this chapter.

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PD-1 Suppresses Development of Humoral Responses That Protect against Tn-Bearing Tumors

Cited by 20 publications

References 45 publications

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

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

PD-L2 Regulates B-1 Cell Antibody Production against Phosphorylcholine through an IL-5–Dependent Mechanism

Evaluation of Virus-Like Particle-Based Tumor-Associated Carbohydrate Immunogen in a Mouse Tumor Model

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