Modulating the T Lymphocyte Immune Response via Secretome Produced miRNA: From Tolerance Induction to the Enhancement of the Anticancer Response

Abstract

T cells are key mediators of graft tolerance/rejection, development of autoimmunity, and the anticancer response. Consequently, differentially modifying the T cell response is a major therapeutic target. Most immunomodulatory approaches have focused on cytotoxic agents, cytokine modulation, monoclonal antibodies, mitogen activation, adoptive cell therapies (including CART cells). However, these approaches do not persistently reorient the systemic immune response thus necessitating continual therapy. Previous murine studies from our laboratory demonstrated that the adoptive transfer of polymer-grafted (PEGylated) allogeneic leukocytes resulted in the induction of a persistent and systemic tolerogenic state. Further analyses demonstrated that miRNA isolated from the secretome of polymermodified or control allogeneic responses effectively induced either a tolerogenic (TA1 miRNA) or proinflammatory (IA1 miRNA) response both in vitro and in vivo that was both systemic and persistent. In a murine Type 1 diabetes autoimmune model, the tolerogenic TA1 therapeutic effectively attenuated the disease process via the systemic upregulation of regulatory T cells while simultaneously downregulating T effector cells. In contrast, the proinflammatory IA1 therapeutic enhanced the anticancer efficacy of naïve PBMC by increasing inflammatory T cells and decreasing regulatory T cells. The successful development of this secretome miRNA approach may prove useful treating both autoimmune diseases and cancer.

Biological Modulation of the Treg:Teff Ratio: From Immunosuppression to Immunoactivation

“…The core component of the biomanufacturing system is, in essence, a twoway mixed lymphocyte reaction (MLR) in which MHC-disparate leukocyte populations (either human PBMC or murine splenocytes) are co-incubated. Previous work from our laboratory demonstrated that the covalent grafting (PEGylation) of methoxy(polyethylene glycol) [mPEG] to one leukocyte population resulted in abrogation of the MHC-mediated proliferation of Teff cells [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42]. Moreover, these studies demonstrated that, consequent to impaired cell:cell communication (Figure 4C), the weak allostimulation induced a tolerogenic/anergic state both in vitro and in vivo ( Figure 4A) [29][30][31][32][33][34]41].…”

“…As demonstrated in Figure 7A, the onset and incidence of diabetes was assessed and correlated with the Treg:Teff ratio of the mice [31][32][33][34][35]. As shown, 75% of the untreated NOD mice, but only 40% of the TA1 treated mice, developed T1D.…”

“…In this chapter we will discuss a novel biomodulatory approach that more effectively, and directly, target the Treg:Teff ratio by increasing or decreasing Treg cells while simultaneously, and inversely, decreasing of increasing Teff subsets (Figure 4). This approach, derived from our work on the polymer-based bioengineering of allogeneic T cells and their use directly, or via the production of acellular microRNA (miRNA), to induce a tolerogenic or proinflammatory state characterized by significant changes in the Treg:Teff ratio [23][24][25][26][27][28][29][30][31][32][33][34][35].…”

“…Biomanufacturing of these immunomodulatory therapeutics was accomplished using a rapid and inexpensive leukocyte allorecognition-based system (Figure 4) [34,35]. The core component of the biomanufacturing system is, in essence, a twoway mixed lymphocyte reaction (MLR) in which MHC-disparate leukocyte populations (either human PBMC or murine splenocytes) are co-incubated.…”

“…Importantly, the active component of the TA1 and IA1 therapeutics are miRNAsnot cytokines or other potential immunomodulatory effectors [31,34,35]. The role of miRNA can be seen by the loss of immunomodulatory activity of TA1 and IA1 conditioned murine plasma upon treatment with RNase ( Figure 6).…”