STING-induced regulatory B cells compromise NK function in cancer immunity.

An immunosuppressive tumour microenvironment is a major obstacle in the control of pancreatic and other solid cancers. Agonists of the stimulator of interferon genes (STING) protein trigger inflammatory innate immune responses to potentially overcome tumour immunosuppression. Although these agonists hold promise as potential cancer therapies, tumour resistance to STING monotherapy has emerged in clinical trials and the mechanism(s) is unclear.

Balance between immunoregulatory B cells and plasma cells drives pancreatic tumor immunity.

Plasma cell responses are associated with anti-tumor immunity and favorable response to immunotherapy. B cells can amplify anti-tumor immune responses through antibody production; yet B cells in patients and tumor-bearing mice often fail to support this effector function. We identify dysregulated transcriptional program in B cells that disrupts differentiation of naive B cells into anti-tumor plasma cells.

Tumor promoting roles of IL-10, TGF-β, IL-4, and IL-35: Its implications in cancer immunotherapy.

Unlabelled: Cytokines play a critical role in regulating host immune response toward cancer and determining the overall fate of tumorigenesis. The tumor microenvironment is dominated mainly by immune-suppressive cytokines that control effector antitumor immunity and promote survival and the proliferation of cancer cells, which ultimately leads to enhanced tumor growth. In addition to tumor cells, the heterogeneous immune cells present within the tumor milieu are the significant source of immune-suppressive cytokines.

B Cell Receptor Signaling and Protein Kinase D2 Support Regulatory B Cell Function in Pancreatic Cancer.

B cells can act as potent suppressors of anti-tumor T cell immunity, presenting a mechanism of resistance to immunotherapy. In pancreatic ductal adenocarcinoma, B cells can display a T cell-suppressive or regulatory phenotype centered on the expression of the cytokine Interleukin 35 (IL-35). While B cell-mediated immunosuppression presents a barrier to anti-tumorigenic T cell function, it is not clear how regulatory B cell function could be targeted, and the signals that promote this suppressive phenotype in B cells are not well understood.

IL-35 Detection in B Cells at the mRNA and Protein Level.

Emerging research suggests that IL-35-producing regulatory B cells accumulate in patients and mouse models of pancreatic cancer, one of the most lethal cancers, characterized by late diagnosis, high mortality, and morbidity. Identification of IL-35-producing B cells can be challenging due to the heterodimeric nature of IL-35 and diversity of cell surface markers that define regulatory B-cell subsets across spectrum of diseases. In this chapter, we describe the methods for the isolation of splenic and tumor-infiltrating murine regulatory B cells and subsequent detection of IL-35 by RT-qPCR and intracellular staining, as well as detection of circulating IL-35 by ELISA.

IL-12 Family Cytokines in Cancer and Immunotherapy.

The IL-12 family cytokines are a group of unique heterodimeric cytokines that include IL-12, IL-23, IL-27, IL-35 and, most recently, IL-39. Recent studies have solidified the importance of IL-12 cytokines in shaping innate and adaptive immune responses in cancer and identified multipronged roles for distinct IL-12 family members, ranging from effector to regulatory immune functions. These cytokines could serve as promising candidates for the development of immunomodulatory therapeutic approaches.

Regulatory B cells in cancer.

Tumorigenesis proceeds through discrete steps where acquisition of genetic lesions and changes in the surrounding microenvironment combine to drive unrestricted neoplastic proliferation and metastasis. The ability of tumor-infiltrating immune cells to promote tumor growth via the provision of signals that enable tumor cell survival and proliferation as well as contribute to immune suppression is an active area of research. Recent efforts have provided us with mechanistic insights into how B cells can positively and negatively regulate immune responses.

Co-expression of master transcription factors determines CD4 T cell plasticity and functions in auto-inflammatory diseases.

Master CD4 T cell lineage determined transcription factors are found to be dysregulated in pathogenesis of autoimmune and inflammatory diseases. CD4 T cells categorized into different lineages based on their functions, cell surface markers and master transcription factors those required for expression of lineage specific cytokines. T-bet, GATA3, RORγt and Foxp3 are major transcription regulators of Th1, Th2, Th17 and Treg cells respectively.

B cell-Derived IL35 Drives STAT3-Dependent CD8 T-cell Exclusion in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy characterized by a paucity of tumor-proximal CD8 T cells and resistance to immunotherapeutic interventions. Cancer-associated mechanisms that elicit CD8 T-cell exclusion and resistance to immunotherapy are not well-known. Here, using a Kras- and p53-driven model of PDA, we describe a mechanism of action for the protumorigenic cytokine IL35 through STAT3 activation in CD8 T cells.

Pancreatic cancer-associated inflammation drives dynamic regulation of p35 and Ebi3.

B cells are important modulators of immune responses both in autoimmunity and cancer. We have previously shown that B regulatory (Breg) cells promote pancreatic cancer via production of IL35, a heterodimeric cytokine comprised of the subunits p35 (Il12a) and Ebi3. However, it is not known how production of IL35 is regulated in vivo in the context of cancer-associated inflammation.

Antitumor Responses in the Absence of Toxicity in Solid Tumors by Targeting B7-H3 via Chimeric Antigen Receptor T Cells.

The high expression across multiple tumor types and restricted expression in normal tissues make B7-H3 an attractive target for immunotherapy. We generated chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR-Ts) and found that B7-H3.

IL35 Hinders Endogenous Antitumor T-cell Immunity and Responsiveness to Immunotherapy in Pancreatic Cancer.

Although successes in cancer immunotherapy have generated considerable excitement, this form of treatment has been largely ineffective in patients with pancreatic ductal adenocarcinoma (PDA). Mechanisms that contribute to the poor antitumor immune response in PDA are not well understood. Here, we demonstrated that cytokine IL35 is a major immunosuppressive driver in PDA and potentiates tumor growth via the suppression of endogenous antitumor T-cell responses.

Chromatin Remodeling Protein SMAR1 Is a Critical Regulator of T Helper Cell Differentiation and Inflammatory Diseases.

T cell differentiation from naïve T cells to specialized effector subsets of mature cells is determined by the iterative action of transcription factors. At each stage of specific T cell lineage differentiation, transcription factor interacts not only with nuclear proteins such as histone and histone modifiers but also with other factors that are bound to the chromatin and play a critical role in gene expression. In this review, we focus on one of such nuclear protein known as tumor suppressor and scaffold matrix attachment region-binding protein 1 (SMAR1) in CD4 T cell differentiation.

Carbon nanospheres mediated delivery of nuclear matrix protein SMAR1 to direct experimental autoimmune encephalomyelitis in mice.

Owing to the suppression of immune responses and associated side effects, steroid based treatments for inflammatory encephalitis disease can be detrimental. Here, we demonstrate a novel carbon nanosphere (CNP) based treatment regime for encephalomyelitis in mice by exploiting the functional property of the nuclear matrix binding protein SMAR1. A truncated part of SMAR1 ie, the DNA binding domain was conjugated with hydrothermally synthesized CNPs.

Regulation of T cell lineage commitment by SMAR1 during inflammatory & autoimmune diseases.

Background & Objectives: CD4 + T cells are involved in abnormal inflammatory responses causing adverse effects to the body. Th17 cells play a major role in immune disorders and the exact mechanism by which CD4 + T cells regulate its effector Th1 and Th17 phenotype at chromatin level is not clearly understood. This study was aimed to understand the role of matrix associated region (MAR) binding protein SMAR1 (scaffold/matrix attachment region binding protein 1) in T cell differentiation during inflammatory and autoimmune condition using SMAR1 transgenic mice as model.

MAR binding protein SMAR1 favors IL-10 mediated regulatory T cell function in acute colitis.

Treg cells are not only crucial for controlling immune responses to autoantigens but also prevent those directed towards commensal pathogens. Control of effector immune responses by Treg cells depend on their capacity to accumulate at inflammatory site and accordingly accommodate to inflammatory environment. Till date, the factors associated with maintaining these aspects of Treg phenotype is not understood properly.