Oh, SangKon

Abstract Description tolerance is the “holy grail” in the fields of transplantation medicine and the treatment of autoimmune diseases. We previously reported that TIGIT+ B cells can efficiently control inflammatory responses while promoting regulatory T cell response via the ligation of CD155 expressed on both T cells and dendritic cells (DCs). Recent studies have also demonstrated that lack of TIGIT expression in B cells can lead to inflammation in the central nervous system in both humans and mice. These findings prompted us to explore whether TIGIT+ B cell therapy model could be developed for the treatment of inflammatory diseases. In this study, we report that TIGIT+ B cells can be generated with replication-incompetent recombinant Adv5 vectors designed to target CD21 on B cells. Those TIGIT+ B cells generated with our novel Adv5 vectors can efficiently control inflammatory T cell responses in vitro by directly acting on T cells and by regulating inflammatory function of DCs. The preclinical efficacy of TIGIT+ B cell therapy model and its underlying mechanisms of action are also investigated using an experimental autoimmune encephalomyelitis model. Data from this study support the clinical development of this novel TIGIT+ B cell therapy model for the treatment of inflammatory diseases. Funding Sources Mayo Clinic Cancer Center Topic Categories Therapeutic Approaches to Autoimmunity (THER)

Pathophysiologic function of B cells in graft rejection has been well recognized in transplantation. B cells promote alloantigen-specific T-cell response and secrete antibodies that can cause antibody-mediated graft failures and rejections. Therefore, strategies targeting B cells, for example, B-cell depletion, have been used for the prevention of both acute and chronic rejections. Interestingly, however, recent mounting evidence indicates that subsets of B cells yet to be further identified can display potent immune regulatory functions, and they contribute to transplantation tolerance and operational tolerance in both experimental and clinical settings, respectively. In this review, we integrate currently available information on B-cell subsets, including T-cell Ig domain and mucin domain 1-positive transitional and T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domain-positive memory B cells, displaying immune regulatory functions, with a focus on transplantation tolerance, by analyzing their mechanisms of action. In addition, we will discuss potential T-cell Ig domain and mucin domain 1-positive and T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domain-positive B cell–based strategies for the enhancement of operational tolerance in transplantation patients.

Abstract Expression of macrophage receptor with collagenous structure (MARCO) by tumor-associated macrophages is associated with poor prognosis of multiple types of cancer. In this article, we report that cancer cells (e.g., breast cancer and glioblastoma cell lines) can upregulate surface MARCO expression on human macrophages not only via IL-6–induced STAT3 activation but also via sphingosine-1-phosphate receptor (S1PR)-mediated IL-6 and IL-10 expression followed by STAT3 activation. We further found that MARCO ligation induces activation of the MEK/ERK/p90RSK/CREB signaling cascade, leading to IL-10 expression followed by STAT3-dependent PD-L1 upregulation. Such MARCO-induced macrophage polarization is accompanied by increased expression of PPARG, IRF4, IDO1, CCL17, and CCL22. Ligation of surface MARCO can thus result in decreased T cell responses mainly by reduction of their proliferation. Taken together, cancer cell–induced MARCO expression and its intrinsic regulatory function within macrophages are, to our knowledge, new aspects of cancer immune evasion mechanisms that need to be further studied in the future.

Abstract TIGIT (T cell immunoreceptor with Ig and ITIM domains) is a co-inhibitory receptor, highly expressed by Tregs, and contributes to the suppressive function of Tregs by limiting pro-inflammatory Th1 and Th17 cell responses. Herein, we report that subsets of human regulatory B cells (Bregs) express surface TIGIT and can thus play a critical role in immune regulation. Using data from human B cell surface arrays and RNA-seq, we identified two major TIGIT+ human Bregs subsets, exhibiting CD24hiCD27+CD39hiIgD+IgMhiCD1chi marginal zone (MZ)-like and CD24hiCD27+CD39+IgD−IgM+CD1c+ memory Bregs. We further demonstrated that TIGIT+ Bregs were also capable of suppressing immune responses by their ability to express not only IL-10 and PD-L1, but also granzyme B and TGFb1. In addition, TIGIT+ Bregs can also suppress immune responses by altering dendritic cell functions. In line with these observations, liver allograft recipients with donor-specific alloantibody (DSA) had significantly lower numbers of TIGIT+ Bregs than those without DSA. Moreover, the frequency of TIGIT+ Bregs correlated with that of CD4+CD25+CD127lo Tregs, while it inversely correlated with the frequency of follicular helper T cells. We thus concluded that TIGIT+ Bregs play critical roles in immune regulation in liver allograft recipients.

Abstract Graft-versus-host disease (GVHD) is one of the major obstacles for the success of allogeneic hematopoietic stem cell transplantation. In this article, we report that the interaction between OX40L and OX40 is of critical importance for both induction and progression of acute GVHD (aGVHD) driven by human T cells. Anti-human OX40L mAb (hOX40L) treatment could thus effectively reduce the disease severity in a xenogeneic-aGVHD model in both preventative and therapeutic modes. Mechanistically, blocking OX40L–OX40 interaction with an anti-hOX40L reduces infiltration of human T cells in target organs, including liver, gut, lung, and skin. It also decreases IL-21– and TNF-producing T cell responses while promoting regulatory T cell responses without compromising the cytolytic activity of CD8+ T cells. Single blockade of hOX40L was thus more effective than dual blockade of IL-21 and TNF in reducing the severity of aGVHD as well as mortality. Data from this study indicate that OX40L–OX40 interactions play a central role in the pathogenesis of aGVHD induced by human T cells. Therapeutic strategies that can efficiently interrupt OX40L–OX40 interaction in patients might have potential to provide patients with an improved clinical benefit.