miR-155 augments CD8 ⁺ T-cell antitumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic γ _c cytokines

Abstract

Lymphodepleting regimens are used before adoptive immunotherapy to augment the antitumor efficacy of transferred T cells by removing endogenous homeostatic "cytokine sinks." These conditioning modalities, however, are often associated with severe toxicities. We found that microRNA-155 (miR-155) enabled tumorspecific CD8 + T cells to mediate profound antitumor responses in lymphoreplete hosts that were not potentiated by immune-ablation. miR-155 enhanced T-cell responsiveness to limited amounts of homeostatic γc cytokines, resulting in delayed cellular contraction and sustained cytokine production. miR-155 restrained the expression of the inositol 5-phosphatase Ship1, an inhibitor of the serinethreonine protein kinase Akt, and multiple negative regulators of signal transducer and activator of transcription 5 (Stat5), including suppressor of cytokine signaling 1 (Socs1) and the protein tyrosine phosphatase Ptpn2. Expression of constitutively active Stat5a recapitulated the survival advantages conferred by miR-155, whereas constitutive Akt activation promoted sustained effector functions. Our results indicate that overexpression of miR-155 in tumorspecific T cells can be used to increase the effectiveness of adoptive immunotherapies in a cell-intrinsic manner without the need for life-threatening, lymphodepleting maneuvers.

Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells

“…The mbIL15-CAR T cells persisted in the absence of CD19 TAA, presumably due to sustained STAT5 phosphorylation. These observations agree with studies where engraftment was enhanced by T cells engineered to (i) express constitutively active STAT5 (46); (ii) express a chimeric cytokine receptor mediating constitutive signaling through CD122 (47); (iii) secrete monomeric recombinant IL-15 (37,48); and (iv) express miR155, which increases AKT and STAT5 signaling (49). Thus, it appears that coordinated signaling with mbIL15 and CAR provides a pathway to improving antitumor effects across a spectrum of tumor burden.…”

Long-Term Persistence of Exhausted CD8 T Cells in Chronic Infection Is Regulated by MicroRNA-155

“…Our transcriptional profiling here suggests that miR-155 reduces inflammatory cytokine signaling (TNF, IL-6, IFN-γ, and TGF-β) and shields T EX cells from the detrimental effects of persistent inflammation. On the other hand, it has been shown that miR-155 enhances the responsiveness of tumor-specific CD8 T cells to common γ-chain cytokines and subsequent phosphorylation of STAT5 (Ji et al, 2015), suggesting that multiple context-dependent mechanisms may exist for miR-155 to enhance CD8 T cell responses. Although our observations suggest a connection between miR-155 and inflammatory and TCR signaling, precisely how miR-155 integrates these events in T EX cells remains to be determined.…”

“…miR-155 enhances CD8 T cell expansion during acute infections and cancer (Gracias et al, 2013; Lind et al, 2013; Lind and Ohashi, 2014; Tsai et al, 2013) and regulates responses to inflammatory and cytokine signals in different settings, such as acutely resolved viral and bacterial infections (Gracias et al, 2013), tumor models (Ji et al, 2015), autoimmunity (O’Connell et al, 2010), and age-dependent inflammation (Hu et al, 2014). Expression of miR-155 is increased in HIV infection, and higher expression of miR-155 correlates with increased disease (Witwer et al, 2012).…”

Heterodimeric IL15 Treatment Enhances Tumor Infiltration, Persistence, and Effector Functions of Adoptively Transferred Tumor-specific T Cells in the Absence of Lymphodepletion

“…Overall, our study confirmed previous findings that lymphopenia is not a prerequisite for effective ACT (46). Several other approaches to improve ACT outcomes in the absence of irradiation and chemotherapy have been recently explored, including the use of antibodies for specific cell type depletion (46), genetically engineered tumor-specific T cells (47), Toll-like receptor (TLR) ligands (48) and other γ-chain cytokines (46,49). One foreseeable advantage of the regimen proposed in this study is the absence of CD4 + T cell ablation.…”