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12 results on '"Johnson, Lexus"'

1. Targeting PARP11 to avert immunosuppression and improve CAR T therapy in solid tumors

Author

Zhang, Hongru, Yu, Pengfei, Tomar, Vivek S., Chen, Xiangjie, Atherton, Matthew J., Lu, Zhen, Zhang, Hong-Guang, Li, Shifeng, Ortiz, Angelica, Gui, Jun, Leu, N. Adrian, Yan, Fangxue, Blanco, Andres, Meyer-Ficca, Mirella L., Meyer, Ralph G., Beiting, Daniel P., Li, Jinyang, Nunez-Cruz, Selene, O’Connor, Roddy S., Johnson, Lexus R., Minn, Andy J., George, Subin S., Koumenis, Constantinos, Diehl, J. Alan, Milone, Michael C., Zheng, Hui, and Fuchs, Serge Y.

Published
2022
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6. Cellular Localization of Inflammatory Signaling as a Determinant of Tumor-Immune Biology

Author

Johnson, Lexus R and Johnson, Lexus R

Abstract

Immune therapies have significantly improved outcomes for cancer patients with poor prognosis, but mechanisms that underlie response or resistance to therapy remain elusive. Inflammatory cytokines such as interferon-gamma (IFNG) augment immune function yet also promote T cell exhaustion through inhibitory ligands such as PDL1. How these opposing effects are integrated in the tumor microenvironment is unclear. We show that while inhibiting tumor IFNG signaling decreases interferon-stimulated genes (ISGs) in cancer cells, it increases ISGs in immune cells by enhancing IFNG produced by exhausted T cells (TEX). In tumors with favorable antigenicity, these TEX mediate rejection. In tumors with neoantigen or MHC-I loss, TEX instead utilize IFNG to drive maturation of innate immune cells, promoting tumor clearance. Thus, interferon signaling in cancer cells and immune cells oppose each other to establish a regulatory relationship that limits both adaptive and innate immune killing. In melanoma and lung cancer patients, perturbation of this relationship is associated with response to immune checkpoint blockade independent of tumor mutational burden. In addition to these suppressive mechanisms, tumor infiltration and antigen loss are common mechanisms that limit effectiveness of T cell responses in solid tumors, in particular chimeric antigen (CAR) T cells. Delivery of pattern recognition receptor agonists is one strategy to improve immune infiltration and prime adaptive immunity; however, targeting these agonists to immune cells is challenging, and off-target signaling in cancer cells can be detrimental as described above. Here, we engineer murine CAR-T cells to deliver RN7SL1, an endogenous RNA that activates RIG-I/MDA5-dependent interferon signaling. RN7SL1 is deployed in extracellular vesicles and preferentially transferred to intratumoral immune cells. Unlike other RNA agonists, RN7SL1 restricts development of myeloid-derived suppressor cells and decreases TGFB expressi

Published
2020

7. Opposing Functions of Interferon Coordinate Adaptive and Innate Immune Responses to Cancer Immune Checkpoint Blockade

Author

Benci, Joseph L., primary, Johnson, Lexus R., additional, Choa, Ruth, additional, Xu, Yuanming, additional, Qiu, Jingya, additional, Zhou, Zilu, additional, Xu, Bihui, additional, Ye, Darwin, additional, Nathanson, Katherine L., additional, June, Carl H., additional, Wherry, E. John, additional, Zhang, Nancy R., additional, Ishwaran, Hemant, additional, Hellmann, Matthew D., additional, Wolchok, Jedd D., additional, Kambayashi, Taku, additional, and Minn, Andy J., additional

Published
2019
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11. Enhancing CAR T function with the engineered secretion of C. perfringensneuraminidase

Author

Durgin, Joseph S., Thokala, Radhika, Johnson, Lexus, Song, Edward, Leferovich, John, Bhoj, Vijay, Ghassemi, Saba, Milone, Michael, Binder, Zev, O'Rourke, Donald M., and O'Connor, Roddy S.

Abstract

Prior to adoptive transfer, CAR T cells are activated, lentivirally infected with CAR transgenes, and expanded over 9 to 11 days. An unintended consequence of this process is the progressive differentiation of CAR T cells over time in culture. Differentiated T cells engraft poorly, which limits their ability to persist and provide sustained tumor control in hematologic as well as solid tumors. Solid tumors include other barriers to CAR T cell therapies, including immune and metabolic checkpoints that suppress effector function and durability. Sialic acids are ubiquitous surface molecules with known immune checkpoint functions. The enzyme C. perfringensneuraminidase (CpNA) removes sialic acid residues from target cells, with good activity at physiologic conditions. In combination with galactose oxidase (GO), NA has been found to stimulate T cell mitogenesis and cytotoxicity in vitro. Here we determine whether CpNAalone and in combination with GO promotes CAR T cell antitumor efficacy. We show that CpNArestrains CAR T cell differentiation during ex vivoculture, giving rise to progeny with enhanced therapeutic potential. CAR T cells expressing CpNAhave superior effector function and cytotoxicity in vitro. In a Nalm-6 xenograft model of leukemia, CAR T cells expressing CpNAshow enhanced antitumor efficacy. Arming CAR T cells with CpNAalso enhanced tumor control in xenograft models of glioblastoma as well as a syngeneic model of melanoma. Given our findings, we hypothesize that charge repulsion via surface glycans is a regulatory parameter influencing differentiation. As T cells engage target cells within tumors and undergo constitutive activation through their CARs, critical thresholds of negative charge may impede cell-cell interactions underlying synapse formation and cytolysis. Removing the dense pool of negative cell-surface charge with CpNAis an effective approach to limit CAR T cell differentiation and enhance overall persistence and efficacy.

Published
2021
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12. BNIP3- and BNIP3L-Mediated Mitophagy Promotes the Generation of Natural Killer Cell Memory.

Author

O'Sullivan TE, Johnson LR, Kang HH, and Sun JC

Subjects
AMP-Activated Protein Kinases metabolism, Animals, Autophagy-Related Proteins, Cells, Cultured, Immunologic Memory genetics, Killer Cells, Natural virology, Membrane Proteins genetics, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mitochondria virology, Mitochondrial Proteins genetics, Reactive Oxygen Species metabolism, TOR Serine-Threonine Kinases metabolism, Ubiquitin-Conjugating Enzymes metabolism, Herpesviridae Infections immunology, Killer Cells, Natural immunology, Membrane Proteins metabolism, Mitochondria metabolism, Mitochondrial Proteins metabolism, Mitophagy genetics, Muromegalovirus immunology
Abstract

Natural killer (NK) cells are innate lymphocytes that possess traits of adaptive immunity, such as clonal expansion, contraction, and generation of long-lived "memory" cells, processes poorly understood at the molecular level. Here, we found that as proliferating NK cells accumulated dysfunctional mitochondria during viral infection, a protective mitophagy pathway was induced during the contraction phase to promote their survival in a reactive oxygen species (ROS)-dependent manner. Inhibition of mechanistic target of rapamycin (mTOR) or activation of AMP-activated protein kinase (AMPK) during the contraction-to-memory phase transition of the antiviral response increased autophagic activity and enhanced memory NK cell numbers through an Atg3-dependent mechanism. Furthermore, we demonstrated a temporally regulated role for mitophagy-inducing proteins BCL2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3) and BNIP3-like (BNIP3L) in the generation of robust NK cell memory. Thus, our study reveals the functional importance of mitophagy during the dynamic response of these cytolytic innate lymphocytes., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Published
2015
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