Liu et al. report that pharmacologically induced CCR2-expressing nonclassical monocytes can infiltrate and regress immunotherapy-resistant cancers by recruiting natural killer cells. The cover image depicts the dynamic interplay between protumor and antitumor immune mechanisms, focusing on the transformation of monocytes in cancer metastasis. Image credit: Ellen Weiss.
BACKGROUND. Antiretroviral therapy (ART) has improved the clinical management of HIV-1 infection. However, little is known about how the latest ART recommendations affect the heterogeneity of HIV-1 reservoir size. METHODS. We used a complete statistical approach to outline parameters underlying diversity in HIV-1 reservoir size in a cohort of 892 people with HIV-1 (PWH) on suppressive ART for >3 years. Total HIV-1-DNA levels were measured in PBMCs using digital droplet PCR (ddPCR). RESULTS. We classified 179 (20%) participants as Low Viral Reservoir Treated (LoViReT, <50 HIV-1-DNA copies/106 PBMCs). Twenty variables were collected to explore their association with the LoViReT phenotype using machine learning approaches. Nadir CD4 and zenith pre-ART viral load were closely associated with LoViReT status, with lower CD4 recovery, shorter time from diagnosis to undetectable viral load, and initiation of treatment with an integrase inhibitor (InSTI)–containing regimen. Initiating ART with any InSTI was also associated with shorter time to undetectable viremia. Locally estimated scatterplot smoothing (LOESS) regression revealed a progressive reduction in the size of the HIV-1 reservoir in individuals who started ART after 2007. Similarly, higher nadir CD4 and shorter time to undetectable viremia were observed when treatment was initiated after that year. CONCLUSION. Our findings demonstrate that the progressive implementation of earlier, universal treatment at diagnosis and the use of InSTIs affect the size of the HIV-1 reservoir. Our work shows that effective management of infection is the first step toward reducing the reservoir and brings us closer to achieving a cure. FUNDING. U.S. National Institutes of Health, Division of AIDS at the National Institute of Allergy and Infectious Diseases, Merck Sharp & Dohme.
Irene González-Navarro, Víctor Urrea, Cristina Gálvez, Maria del Carmen Garcia-Guerrero, Sara Morón-López, Maria C. Puertas, Eulàlia Grau, Beatriz Mothe, Lucía Bailón, Cristina Miranda, Felipe García, Lorna Leal, Linos Vandekerckhove, Vincent C. Marconi, Rafick P. Sekaly, Bonaventura Clotet, Javier Martinez-Picado, Maria Salgado
Despite the revolutionary achievements of chimeric antigen receptor (CAR) T cell therapy in treating cancers, especially leukemia, several key challenges still limit its therapeutic efficacy. Of particular relevance is the relapse of cancer in large part, as a result of exhaustion and short persistence of CAR-T cells in vivo. IL-2-inducible T cell kinase (ITK) is a critical modulator of the strength of T-cell receptor (TCR) signaling, while its role in CAR signaling is unknown. By electroporation of clustered regularly interspaced short palindromic repeats (CRISPR) associated protein 9 (Cas9) ribonucleoprotein (RNP) complex into CAR-T cells, we successfully deleted ITK in CD19-CAR-T cells with high efficiency. Bulk and single-cell RNA sequencing (scRNA-seq) analyses revealed down-regulation of exhaustion and up-regulation of memory gene signatures in ITK-deficient CD19-CAR-T cells. Our results further demonstrated a significant reduction of T cell exhaustion and enhancement of T cell memory, with significant improvement of CAR-T cell expansion and persistence both in vitro and in vivo. Moreover, ITK-deficient CD19-CAR-T cells showed better control of tumor relapse. Our work provides a promising strategy of targeting ITK to develop sustainable CAR-T products for clinical use.
Zheng Fu, Zineng Huang, Hao Xu, Qingbai Liu, Jing Li, Keqing Song, Yating Deng, Yujia Tao, Huifang Zhang, Peilong Wang, Heng Li, Yue Sheng, Aijun Zhou, Lianbin Han, Yan Fu, Chen-Zhi Wang, Saurav Kumar Choudhary, Kaixiong Ye, Gianluca Veggiani, Zhihong Li, Avery August, Weishan Huang, Qiang Shan, Hongling Peng
Nerve growth factor (NGF) monoclonal antibodies inhibit chronic pain yet failed to gain approval due to worsened joint damage in osteoarthritis patients. We report that neuropilin-1 (NRP1) is a co-receptor for NGF and tropomyosin-related kinase A (TrkA) pain signaling. NRP1 was coexpressed with TrkA in human and mouse nociceptors. NRP1 inhibitors suppressed NGF-stimulated excitation of human and mouse nociceptors and NGF-evoked nociception in mice. NRP1 knockdown inhibited NGF/TrkA signaling, whereas NRP1 overexpression enhanced signaling. NGF bound NRP1 with high affinity and interacted with and chaperoned TrkA from the biosynthetic pathway to the plasma membrane and endosomes, enhancing TrkA signaling. Molecular modeling suggested that C-terminal R/KXXR/K NGF motif interacts with extracellular “b” NRP1 domain within a plasma membrane NGF/TrkA/NRP1 of 2:2:2 stoichiometry. G Alpha Interacting Protein C-terminus 1 (GIPC1), which scaffolds NRP1 and TrkA to myosin VI, colocalized in nociceptors with NRP1/TrkA. GIPC1 knockdown abrogated NGF-evoked excitation of nociceptors and pain-like behavior. Thus, NRP1 is a nociceptor-enriched co-receptor that facilitates NGF/TrkA pain signaling. NRP binds NGF and chaperones TrkA to the plasma membrane and signaling endosomes via GIPC1 adaptor. NRP1 and GIPC1 antagonism in nociceptors offers a long-awaited non-opioid alternative to systemic antibody NGF sequestration for the treatment of chronic pain.
Chloe J. Peach, Raquel Tonello, Elisa Damo, Kimberly Gomez, Aida Calderon-Rivera, Renato Bruni, Harsh Bansia, Laura Maile, Ana-Marie Manu, Hyunggu Hahn, Alex R.B. Thomsen, Brian L. Schmidt, Steve Davidson, Amedee des Georges, Rajesh Khanna, Nigel W. Bunnett
The SLC6A1 gene encodes the gamma-aminobutyric acid (GABA) transporter GAT-1, the deficiency of which is associated with infantile encephalopathy with intellectual disability. We designed two AAV9 vectors, with either the JeT or MeP promoter, and conducted preclinical gene therapy studies using heterozygous and homozygous Slc6a1 KO mice at different developmental ages and various routes of administration. Neonatal intracerebroventricular administration of either vector resulted in significantly normalized EEG patterns in Slc6a1-/- or Slc6a1+/- mice, as well as improvement in several behavioral phenotypes of Slc6a1-/- mice. However, some mortality and adverse effects were observed in neonatal-treated mice. Intrathecal administration of either vector at postnatal day (PND) 5 normalized EEG patterns in Slc6a1+/- mice, but in Slc6a1-/- mice the treatment only rescued nest building without impact on EEG. Both vectors were well-tolerated in all mice treated at PND5 or later (including WT mice), up to 1 year post-injection. Overall, our data demonstrate compelling efficacy when mice are treated at an early development age. We also identified that outside of the neonatal treatment window, the severe homozygous KO model is more refractory to treatment, whereas our treatments in the heterozygous mice, which genotypically match human patients, have resulted in stronger benefits.
Weirui Guo, Matthew Rioux, Frances Shaffo, Yuhui Hu, Ze Yu, Chao Xing, Steven J. Gray
The development of pathogenic autoreactive CD4+ T cells, particularly in the context of impaired signaling, remains poorly understood. Unraveling how defective signaling pathways contribute to their activation and persistence is crucial for identifying new therapeutic targets. We profiled a highly arthritogenic subset of naïve CD4+ T cells using bulk and single-cell RNA and TCR sequencing from SKG mice, which develop CD4+ T cell mediated autoimmune arthritis driven by a hypomorphic mutation in Zap70—a key TCR signaling kinase. Despite impaired signaling, these cells exhibit heightened expression of T cell activation and cytokine signaling genes, but diminished expression of a subset of tolerogenic markers (Izumo1r, Tnfrsf9, Cd5, S100a11) compared to wild-type cells. The arthritogenic cells show an enrichment for TCR variable beta (Vβ) chains targeting superantigens from the endogenous mouse mammary tumor virus (MMTV) but exhibit diminished induction of tolerogenic markers following peripheral antigen encounter, contrasting with the robust induction of negative regulators seen in wild-type cells. In arthritic joints, cells expressing superantigen-reactive Vβs expand alongside detectable MMTV proviruses. Antiretroviral treatment and superantigen-reactive T cell depletion curtail SKG arthritis, suggesting that endogenous retroviruses disrupt peripheral tolerance and promote the activation and differentiation of self-reactive CD4+ T cells into pathogenic effector cells.
Elizabeth E. McCarthy, Steven Yu, Noah Perlmutter, Yuka Nakao, Ryota Naito, Charles Lin, Vivienne Riekher, Joe DeRisi, Chun Jimmie Ye, Arthur Weiss, Judith F. Ashouri
JCI celebrates a century of publishing scientific discoveries with a special collection highlighting major innovations in medicine and key contributing mechanistic studies.
Substance use disorders are characterized by heavy, regular use of one or more psychoactive substances, such as alcohol, nicotine, opioids, cannabis, and stimulants, as well as the development of tolerance and loss of control over use, risk-taking behavior, and physiological dependence. Misuse of psychoactive substances constitutes a growing worldwide burden with broad-ranging health consequences. In this review series, curated by Dr. Henry R. Kranzler, reviews will provide detailed updates on studies of the genetics, biology, and evolving treatment of substance use disorders.
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