Resisting T cell attack: tumor-cell-intrinsic defense and reparation mechanisms DOI Creative Commons
Brienne McKenzie, Salvatore Valitutti

Trends in cancer, Journal Year: 2022, Volume and Issue: 9(3), P. 198 - 211

Published: Dec. 31, 2022

Cytotoxic T lymphocytes (CTLs) are antigen-specific killer cells equipped to identify and eliminate host that have been altered through infection or transformation. Both chimeric antigen-receptor (CAR) cell therapies immune checkpoint blockade (ICB) based on successful elimination of tumor by cytotoxic effectors. In this opinion article, we outline cell-intrinsic mechanisms which defend against CTLs, highlighting pathways confer resistance proposing opportunities for combination therapies. We discuss how exogenous killing entities [e.g., supramolecular attack particles (SMAPs)] offer a novel strategy circumvent cellular mechanisms. Our article highlights the importance identifying, quantifying, targeting defense at interface between CTLs as critical consideration in development immunotherapy approaches.

Language: Английский

Orthogonal cytokine engineering enables novel synthetic effector states escaping canonical exhaustion in tumor-rejecting CD8+ T cells DOI Creative Commons
Jesús Corría-Osorio, Santiago J. Carmona, Evangelos Stefanidis

et al.

Nature Immunology, Journal Year: 2023, Volume and Issue: 24(5), P. 869 - 883

Published: April 20, 2023

To date, no immunotherapy approaches have managed to fully overcome T-cell exhaustion, which remains a mandatory fate for chronically activated effector cells and major therapeutic challenge. Understanding how reprogram CD8+ tumor-infiltrating lymphocytes away from exhausted states an elusive goal. Our work provides evidence that orthogonal gene engineering of T secrete interleukin (IL)-2 variant binding the IL-2Rβγ receptor alarmin IL-33 reprogrammed adoptively transferred acquire novel, synthetic state, deviated canonical exhaustion displayed superior functions. These successfully overcame homeostatic barriers in host led-in absence lymphodepletion or exogenous cytokine support-to high levels engraftment tumor regression. unlocks new opportunity rationally endowed with ability avoid control advanced solid tumors.

Language: Английский

Citations

32
Reversing T Cell Dysfunction to Boost Glioblastoma Immunotherapy by Paroxetine‐Mediated GRK2 Inhibition and Blockade of Multiple Checkpoints through Biomimetic Nanoparticles DOI Creative Commons
Tingting Wang, Hao Zhang,

Yaobao Han

et al.

Advanced Science, Journal Year: 2023, Volume and Issue: 10(9)

Published: Jan. 25, 2023

Abstract T cell dysfunction‐induced tumor immune escape is particularly severe in glioblastoma (GBM), and significantly affects the efficacy of immunotherapy. It crucial to innovatively reverse dysfunction for improving GBM Herein, remarkably reversed immunotherapy boosted by repurposing U. S. Food Drug Administration‐approved antidepressant paroxetine (PX) with biomimetic nanoparticles (CS‐J@CM/6 NPs). The PX successfully applied abrogate sequestration bone marrow GBM‐bearing mice increase their infiltration tumor. NPs are composed ultrasmall Cu 2− x Se NPs, JQ1, membrane modified CD6, efficiently delivered into through specific interactions between CD6 activated leukocyte adhesion molecule. They ameliorate double roles loaded which simultaneously decreases expression PD‐1 TIM‐3 on cells, PD‐L1 cells. NP also induces immunogenic death cells activate response. synergistic CS‐J@CM/6 notably enhance survival mice. This work provides new insights “old drugs” advanced NPs.

Language: Английский

Citations

30
Single-cell multi-omics of mitochondrial DNA disorders reveals dynamics of purifying selection across human immune cells DOI
Caleb A. Lareau, Sonia M. Dubois,

Frank A. Buquicchio

et al.

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(7), P. 1198 - 1209

Published: June 29, 2023

Language: Английский

Citations

26
Ileitis promotes MASLD progression via bile acid modulation and enhanced TGR5 signaling in ileal CD8+ T cells DOI
Chang Zheng, Lei Wang,

Tianhui Zou

et al.

Journal of Hepatology, Journal Year: 2024, Volume and Issue: 80(5), P. 764 - 777

Published: Jan. 4, 2024

Language: Английский

Citations

15
Defective mitochondria remodelling in B cells leads to an aged immune response DOI Creative Commons

Marta Iborra-Pernichi,

Jonathan Ruiz García,

María Velasco de la Esperanza

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 22, 2024

Abstract The B cell response in the germinal centre (GC) reaction requires a unique bioenergetic supply. Although mitochondria are remodelled upon antigen-mediated receptor stimulation, mitochondrial function cells is still poorly understood. To gain better understanding of role function, here we generate mice with cell-specific deficiency Tfam, transcription factor necessary for biogenesis. Tfam conditional knock-out (KO) display blockage GC and bias differentiation towards memory aged-related cells, hallmarks an aged immune response. Unexpectedly, blocked KO not caused by defects supply but associated defect remodelling lysosomal compartment cells. Our results may thus describe lysosome regulation downstream antigen presentation during reaction, dysruption which manifested as

Language: Английский

Citations

10
Optimizing Spectronaut Search Parameters to Improve Data Quality with Minimal Proteome Coverage Reductions in DIA Analyses of Heterogeneous Samples DOI Creative Commons
Christa P. Baker, Roland Bruderer, James Abbott

et al.

Journal of Proteome Research, Journal Year: 2024, Volume and Issue: 23(6), P. 1926 - 1936

Published: May 1, 2024

Data-independent acquisition has seen breakthroughs that enable comprehensive proteome profiling using short gradients. As the coverage continues to increase, quality of data generated becomes much more relevant. Using Spectronaut, we show default search parameters can be easily optimized minimize occurrence false positives across different samples. an immunological infection model system demonstrate impact adjusting settings, analyzed Mus musculus macrophages and compared their spiked withCandida albicans. This experimental enabled identification "false positives" as Candida albicans peptides proteins should not present in musculus-only We reduced positive" identifications by 89% at peptide protein level, thereby considerably increasing data. also these incurred a moderate cost, only reducing overall number "true each biological replicate <6.7% both level. believe value our updated extends beyond two-organism analysis would great any DIA experiment analyzing heterogeneous populations cell types or tissues.

Language: Английский

Citations

9
Resetting the Hsc70-mediated lysosomal degradation of PD-L1 via a supramolecular meso peptide for the restoration of acquired anti-tumor T cell immunity DOI Creative Commons
Yujia Zhao, Dan Liu, Wenguang Yang

et al.

Journal of Nanobiotechnology, Journal Year: 2025, Volume and Issue: 23(1)

Published: Feb. 4, 2025

The reduction of cellular PD-L1 abundance through lysosomal degradation is recognized as essential for effective and sustained targeting PD-L1-dependent immune evasion in cancer. While Hsc70 can interact with to promote its degradation, the overexpression CMTM6 competitively inhibits this interaction, leading blockade degradation. To overcome issue, a meso chimeric peptide PEPPDL1 was designed specifically bind PD-1 binding domain instead Hsc70/CMTM6 domain, while also facilitate dragging into Hsc70-mediated chaperone-mediated autophagy (CMA), thereby achieving In order enable internalization tumor cells, supramolecular engineering techniques were employed terminal modification involving sulfydryl monovalent gold ion (Au(I)), both facilitating self-assembly modified nanospheres termed CTAC-PDL1 driven by aurophilic interaction. Furthermore, based on bioinformatics analysis mRNA expression data from 30 types tumors obtained TCGA database, malignant melanoma identified most suitable indication due specific characteristics immune. As expected, effectively reactivated consequently restored anti-tumor T cell immunity B16F10-derived mouse model maintaining favorable safety profile. Overall, work not only presents an alternative approach cancer evasion, but provides modularized strategy discovering regulators target proteins various diseases.

Language: Английский

Citations

1
Fueling sentinel node via reshaping cytotoxic T lymphocytes with a flex-patch for post-operative immuno-adjuvant therapy DOI Creative Commons
Bei Li, Guohao Wang, Kai Miao

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: May 2, 2023

Abstract Clinical updates suggest conserving metastatic sentinel lymph nodes (SLNs) of breast cancer (BC) patients during surgery; however, the immunoadjuvant potential this strategy is unknown. Here we leverage an immune-fueling flex-patch to animate SLNs with personalized antitumor immunity. The implanted on postoperative wound and spatiotemporally releases immunotherapeutic anti-PD-1 antibodies (aPD-1) adjuvants (magnesium iron-layered double hydroxide, LDH) into SLN. Genes associated citric acid cycle oxidative phosphorylation are enriched in activated CD8 + T cells (CTLs) from SLNs. Delivered aPD-1 LDH confer CTLs upregulated glycolytic activity, promoting CTL activation cytotoxic killing via metal cation-mediated shaping. Ultimately, patch-driven could long-termly maintain tumor antigen-specific memory, protecting against high-incidence BC recurrence female mice. This study indicates a clinical value SLN therapy.

Language: Английский

Citations

20
A Genetic Bottleneck of Mitochondrial DNA During Human Lymphocyte Development DOI Creative Commons
Zhongjie Tang,

Zhaolian Lu,

Baizhen Chen

et al.

Molecular Biology and Evolution, Journal Year: 2022, Volume and Issue: 39(5)

Published: April 27, 2022

Mitochondria are essential organelles in eukaryotic cells that provide critical support for energetic and metabolic homeostasis. Although the elimination of pathogenic mitochondrial DNA (mtDNA) mutations somatic has been observed, mechanisms to maintain proper functions despite their mtDNA mutation load poorly understood. In this study, we analyzed more than 30,000 single human peripheral bone marrow mononuclear cells. We observed a significant overrepresentation homoplasmic B, T, natural killer (NK) lymphocytes. Intriguingly, overall mutational burden was lower hematopoietic progenitors myeloid This characteristic landscape indicates genetic bottleneck during lymphoid development, as confirmed with single-cell datasets from multiple platforms individuals. further demonstrated replication lags behind cell proliferation both pro-B pre-B progenitor cells, thus likely causing by diluting copies per cell. Through computational simulations approximate Bayesian computation (ABC), recapitulated lymphocyte-specific estimated minimal <30 NK lineages. Our integrative analysis revealed novel process lymphoid-specific bottleneck, illuminating potential mechanism used highly metabolically active immune limit load.

Language: Английский

Citations

27
Landscapes and mechanisms of CD8+ T cell exhaustion in gastrointestinal cancer DOI Creative Commons

Jiatong Ding,

Kangping Yang,

Haonan Zhou

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: April 25, 2023

CD8 + T cells, a cytotoxic lymphocyte, are key component of the tumor immune system, but they enter hyporeactive cell state in long-term chronic inflammation, and how to rescue this depleted is direction research. Current studies on exhaustion have found that mechanisms responsible for their heterogeneity differential kinetics may be closely related transcription factors epigenetic regulation, which serve as biomarkers potential immunotherapeutic targets guide treatment. Although importance immunotherapy cannot overstated, pointed out gastric cancer tissues better anti-tumor composition compared other tissues, indicate gastrointestinal cancers more promising prospects development precision-targeted immunotherapy. Therefore, present study will focus involved exhaustion, then review landscapes well clinical applications, provide clear vision future immunotherapies.

Language: Английский

Citations

16