Disorders of the JAK/STAT Pathway in T Cell Lymphoma Pathogenesis: Implications for Immunotherapy.

Common gamma receptor-dependent cytokines and their JAK/STAT pathways play pivotal roles in T cell immunity. Abnormal activation of this system was pervasive in diverse T cell malignancies assessed by pSTAT3/pSTAT5 phosphorylation. Activating mutations were described in some but not all cases. JAK1 and STAT3 were required for proliferation and survival of these T cell lines whether or not JAKs or STATs were mutated. Activating JAK and STAT mutations were not sufficient to initiate leukemic cell proliferation but rather only augmented signals from upstream in the cytokine pathway. Activation required the full pathway, including cytokine receptors acting as scaffolds and docking sites for required downstream JAK/STAT proteins. JAK kinase inhibitors have depressed leukemic T cell line proliferation. The insight that JAK/STAT system activation is pervasive in T cell malignancies suggests novel therapeutic approaches that include antibodies to common gamma cytokines, inhibitors of cytokine-receptor interactions, and JAK kinase inhibitors that may revolutionize therapy for T cell malignancies.

The tertiary structure of γc cytokines dictates receptor sharing.

The γc family of cytokines comprising interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-2 is an important group of 4-helix bundle cytokines that signals through receptors incorporating the common gamma chain (γc). These cytokines are involved in lymphocyte biology and their specific functions are contingent on binding to cognate receptor chains. Here, we examined the structural relationships between γc cytokines, aiming to understand the basis for receptor chain usage and sharing. To that end, we obtained tertiary structures of human and mouse γc cytokines plus two other related cytokines, IL-13 and TSLP, which share receptors with IL-4 and IL-7, respectively. Subsequently, we compared the cytokine 3D-structures introducing a structural similarity score that grouped γc cytokines in a manner that mirrored the relationships dictated by receptor sharing. Unlike previously thought, we identified that IL-9 is more closely related to IL-2 and IL-15 than to IL-7, which is actually the most distant member of the γc family of cytokines. Moreover, we found that all the members of the γc family of cytokines share the topology of short-chain 4-helix bundle cytokines but IL-7 that with TSLP has the topology of long-chain 4-helix bundle cytokines. We also carried out Maximun-Likehood and Bayesian phylogenetic analyses that supported these results at the amino acid sequence level. Overall, our findings are of paramount relevance to understand receptor sharing among γc cytokines and can lead to the discovery of new cytokine receptor partners.

Pharmacologic control of homeostatic and antigen-driven proliferation to target HIV-1 persistence.

The presence of latent human immunodeficiency virus 1 (HIV-1) in quiescent memory CD4 + T cells represents a major barrier to viral eradication. Proliferation of memory CD4 + T cells is the primary mechanism that leads to persistence of the latent reservoir, despite effective antiretroviral therapy (ART). Memory CD4 + T cells are long-lived and can proliferate through two mechanisms: homeostatic proliferation via γc-cytokine stimulation or antigen-driven proliferation. Therefore, therapeutic modalities that perturb homeostatic and antigen-driven proliferation, combined with ART, represent promising strategies to reduce the latent reservoir. In this study, we investigated a library of FDA-approved oncology drugs to determine their ability to inhibit homeostatic and/or antigen-driven proliferation. We confirmed potential hits by evaluating their effects on proliferation in memory CD4 + T cells from people living with HIV-1 on ART (PLWH) and interrogated downstream signaling of γc-cytokine stimulation. We found that dasatinib and ponatinib, tyrosine kinase inhibitors, and trametinib, a MEK inhibitor, reduced both homeostatic and antigen-driven proliferationby >65%, with a reduction in viability <45%, ex vivo. In memory CD4 + T cells from PLWH, only dasatinib restricted both homeostatic and antigen-driven proliferation and prevented spontaneous rebound, consistent with promoting a smaller reservoir size. We show that dasatinib restricts IL-7 induced proliferation through STAT5 phosphorylation inhibition. Our results establish that the anti-cancer agent dasatinib is an exciting candidate to be used as an anti-proliferative drug in a clinical trial, since it efficiently blocks proliferation and iswell tolerated in patients with chronic myeloid leukemia (CML).

miR-155 releases the brakes on antitumor T cells.

Homeostatic γC cytokines are essential to support the expansion and function of tumor-specific T cells, but their effects are constrained by suppressor of cytokine signaling (SOCS) proteins as well as phosphoinositide and tyrosine-specific phosphatases. The microRNA miR-155 counteracts these inhibitory hurdles to potentiate intracellular cytokine signaling and T cell antitumor immunity.