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Abstract

Triple-negative breast cancer (TNBC) includes basal-like and claudin-low subtypes for which no specific treatment is currently available. Although the retinoblastoma tumor-suppressor gene (RB1) is frequently lost together with TP53 in TNBC, it is not directly targetable. There is thus great interest in identifying vulnerabilities downstream of RB1 that can be therapeutically exploited. Here, we determined that combined inactivation of murine Rb and p53 in diverse mammary epithelial cells induced claudin-low–like TNBC with Met, Birc2/3-Mmp13-Yap1, and Pvt1-Myc amplifications. Gene set enrichment analysis revealed that Rb/p53-deficient tumors showed elevated expression of the mitochondrial protein translation (MPT) gene pathway relative to tumors harboring p53 deletion alone. Accordingly, bioinformatic, functional, and biochemical analyses showed that RB1-E2F complexes bind to MPT gene promoters to regulate transcription and control MPT. Additionally, a screen of US Food and Drug Administration–approved (FDA-approved) drugs identified the MPT antagonist tigecycline (TIG) as a potent inhibitor of Rb/p53-deficient tumor cell proliferation. TIG preferentially suppressed RB1-deficient TNBC cell proliferation, targeted both the bulk and cancer stem cell fraction, and strongly attenuated xenograft growth. It also cooperated with sulfasalazine, an FDA-approved inhibitor of cystine xCT antiporter, in culture and xenograft assays. Our results suggest that RB1 deficiency promotes cancer cell proliferation in part by enhancing mitochondrial function and identify TIG as a clinically approved drug for RB1-deficient TNBC.

Authors

Robert A. Jones, Tyler J. Robinson, Jeff C. Liu, Mariusz Shrestha, Veronique Voisin, YoungJun Ju, Philip E.D. Chung, Giovanna Pellecchia, Victoria L. Fell, SooIn Bae, Lakshmi Muthuswamy, Alessandro Datti, Sean E. Egan, Zhe Jiang, Gustavo Leone, Gary D. Bader, Aaron Schimmer, Eldad Zacksenhaus

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Abstract

Studies of the genetic factors associated with human autoimmune disease suggest a multigenic origin of susceptibility; however, how these factors interact and through which tolerance pathways they operate generally remain to be defined. One key checkpoint occurs through the activity of the autoimmune regulator AIRE, which promotes central T cell tolerance. Recent reports have described a variety of dominant-negative AIRE mutations that likely contribute to human autoimmunity to a greater extent than previously thought. In families with these mutations, the penetrance of autoimmunity is incomplete, suggesting that other checkpoints play a role in preventing autoimmunity. Here, we tested whether a defect in LYN, an inhibitory protein tyrosine kinase that is implicated in systemic autoimmunity, could combine with an Aire mutation to provoke organ-specific autoimmunity. Indeed, mice with a dominant-negative allele of Aire and deficiency in LYN spontaneously developed organ-specific autoimmunity in the eye. We further determined that a small pool of retinal protein–specific T cells escaped thymic deletion as a result of the hypomorphic Aire function and that these cells also escaped peripheral tolerance in the presence of LYN-deficient dendritic cells, leading to highly destructive autoimmune attack. These findings demonstrate how 2 distinct tolerance pathways can synergize to unleash autoimmunity and have implications for the genetic susceptability of autoimmune disease.

Authors

Irina Proekt, Corey N. Miller, Marion Jeanne, Kayla J. Fasano, James J. Moon, Clifford A. Lowell, Douglas B. Gould, Mark S. Anderson, Anthony L. DeFranco

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Abstract

NK cells are innate lymphocytes with protective functions against viral infections and tumor formation. Human NK cells carry inhibitory killer cell Ig-like receptors (KIRs), which recognize distinct HLAs. NK cells with KIRs for self-HLA molecules acquire superior cytotoxicity against HLA tumor cells during education for improved missing-self recognition. Here, we reconstituted mice with human hematopoietic cells from donors with homozygous KIR ligands or with a mix of hematopoietic cells from these homozygous donors, allowing assessment of the resulting KIR repertoire and NK cell education. We found that co-reconstitution with 2 KIR ligand–mismatched compartments did not alter the frequency of KIR-expressing NK cells. However, NK cell education was diminished in mice reconstituted with parallel HLA compartments due to a lack of cognate HLA molecules on leukocytes for the corresponding KIRs. This change in NK cell education in mixed human donor–reconstituted mice improved NK cell–mediated immune control of EBV infection, indicating that mixed hematopoietic cell populations could be exploited to improve NK cell reactivity against leukotropic pathogens. Taken together, these findings indicate that leukocytes lacking cognate HLA ligands can disarm KIR+ NK cells in a manner that may decrease HLA tumor cell recognition but allows for improved NK cell–mediated immune control of a human γ-herpesvirus.

Authors

Vanessa Landtwing, Ana Raykova, Gaetana Pezzino, Vivien Béziat, Emanuela Marcenaro, Claudine Graf, Alessandro Moretta, Riccarda Capaul, Andrea Zbinden, Guido Ferlazzo, Karl-Johan Malmberg, Obinna Chijioke, Christian Münz

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Abstract

Potent CD19-directed immunotherapies, such as chimeric antigen receptor T cells (CART) and blinatumomab, have drastically changed the outcome of patients with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). However, CD19-negative relapses have emerged as a major problem that is observed in approximately 30% of treated patients. Developing approaches to preventing and treating antigen-loss escapes would therefore represent a vertical advance in the field. Here, we found that in primary patient samples, the IL-3 receptor α chain CD123 was highly expressed on leukemia-initiating cells and CD19-negative blasts in bulk B-ALL at baseline and at relapse after CART19 administration. Using intravital imaging in an antigen-loss CD19-negative relapse xenograft model, we determined that CART123, but not CART19, recognized leukemic blasts, established protracted synapses, and eradicated CD19-negative leukemia, leading to prolonged survival. Furthermore, combining CART19 and CART123 prevented antigen-loss relapses in xenograft models. Finally, we devised a dual CAR-expressing construct that combined CD19- and CD123-mediated T cell activation and demonstrated that it provides superior in vivo activity against B-ALL compared with single-expressing CART or pooled combination CART. In conclusion, these findings indicate that targeting CD19 and CD123 on leukemic blasts represents an effective strategy for treating and preventing antigen-loss relapses occurring after CD19-directed therapies

Authors

Marco Ruella, David M. Barrett, Saad S. Kenderian, Olga Shestova, Ted J. Hofmann, Jessica Perazzelli, Michael Klichinsky, Vania Aikawa, Farzana Nazimuddin, Miroslaw Kozlowski, John Scholler, Simon F. Lacey, Jan J. Melenhorst, Jennifer J.D. Morrissette, David A. Christian, Christopher A. Hunter, Michael Kalos, David L. Porter, Carl H. June, Stephan A. Grupp, Saar Gill

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August 2016

126 8 cover

August 2016 Issue

On the cover:
CAR T cells with intrinsic checkpoint blockade

On page 3130, Cherkassky et al. demonstrate that CAR T cells with intrinsic checkpoint blockade mediated by expression of a dominant negative PD-1 receptor improve effector function and overall survival. The cover image is a false-colored electron micrograph of CAR T cells (blue) attacking and killing cancer cells (magenta).

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Jci tm 2016 08

August 2016 JCI This Month

JCI This Month is a digest of the research, reviews, and other features published each month.

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Review Series - More

Extracellular Vesicles

Series edited by Laurence Zitvogel

Cell-to-cell communication is an essential component in multicellular organisms, allowing for rapid, coordinated responses to changes within the environment. Classical signaling mediators include direct cell-cell contact as well as secreted factors, such as cytokines, metabolites, and hormones. In the past decade, extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, have emerged as important mediators of intercellular communication. EVs are double-membrane vesicles containing cargoes of multiple proteins, lipids, and nucleic acids, which are derived from their cells of origin, and EV cargoes can change depending on the status of their originating cells. Importantly, EVs are found in all body fluids and can carry their cargoes to distant sites within the body as well as neighboring cells. Reviews in this series discuss the role of EV-mediated signaling in physiological and pathophysiological conditions, including infection, host immune responses, and cancer. Additionally, these reviews cover the potential clinical use of EVs as therapeutics and diagnostic biomarkers.

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