Deciphering molecular and cellular ex vivo responses to bispecific antibodies PD1-TIM3 and PD1-LAG3 in human tumors DOI Creative Commons
Marina Natoli, Klas Hatje,

Pratiksha Gulati

et al.

Journal for ImmunoTherapy of Cancer, Journal Year: 2022, Volume and Issue: 10(11), P. e005548 - e005548

Published: Nov. 1, 2022

Background Next-generation cancer immunotherapies are designed to broaden the therapeutic repertoire by targeting new immune checkpoints including lymphocyte-activation gene 3 (LAG-3) and T cell immunoglobulin mucin-domain containing-3 (TIM-3). Yet, molecular cellular mechanisms which either receptor functions mediate its inhibitory effects still poorly understood. Similarly, little is known on differential of dual, compared with single, checkpoint inhibition. Methods We here performed in-depth characterization, multicolor flow cytometry, single RNA sequencing multiplex supernatant analysis, using tumor suspensions from patients treated ex vivo novel bispecific antibodies programmed death protein 1 (PD-1) TIM-3 (PD1-TIM3), PD-1 LAG-3 (PD1-LAG3), or anti-PD-1. Results identified patient samples were responsive PD1-TIM3, PD1-LAG3 anti-PD-1 an in vitro approach, validated analysis 659 soluble proteins enrichment for responder signature. found increased abundance activated (HLA-DR + CD25 GranzymeB ) CD8 subset proliferating cells, response antibody treatment. Bispecific antibodies, but not anti-PD-1, significantly a natural killer subset, exhibited tissue-residency Key phenotypic transcriptional changes occurred CXCL13 CD4 all treatments, interleukin-17 secretion signaling toward plasma cells. Interestingly, upregulation was detected as unique pharmacodynamic effect mediated PD1-LAG3, PD1-TIM3 Conclusions Our system reliably assessed responses co-targeting together patients’ infiltrating cells revealed imprinting formats currently tested early clinical trials.

Language: Английский

Myeloid C-type lectin receptors in innate immune recognition DOI Creative Commons
Caetano Reis e Sousa, Sho Yamasaki, Gordon D. Brown

et al.

Immunity, Journal Year: 2024, Volume and Issue: 57(4), P. 700 - 717

Published: April 1, 2024

C-type lectin receptors (CLRs) expressed by myeloid cells constitute a versatile family of that play key role in innate immune recognition. Myeloid CLRs exhibit remarkable ability to recognize an extensive array ligands, from carbohydrates and beyond, encompass pattern-associated molecular patterns (PAMPs), damage-associated (DAMPs), markers altered self. These receptors, classified into distinct subgroups, pivotal roles recognition modulation responses. Their intricate signaling pathways orchestrate spectrum cellular responses, influencing processes such as phagocytosis, cytokine production, antigen presentation. Beyond their contributions host defense viral, bacterial, fungal, parasitic infections, have been implicated non-infectious diseases cancer, allergies, autoimmunity. A nuanced understanding CLR interactions with endogenous microbial triggers is starting uncover the context-dependent nature immunity, implications for therapeutic intervention.

Language: Английский

Citations

29
Package delivered: folate receptor-mediated transporters in cancer therapy and diagnosis DOI Creative Commons
Mohsen Ahmadi, Christoph A. Ritter, Thomas von Woedtke

et al.

Chemical Science, Journal Year: 2024, Volume and Issue: 15(6), P. 1966 - 2006

Published: Jan. 1, 2024

Neoplasias pose a significant threat to aging society, underscoring the urgent need overcome limitations of traditional chemotherapy through pioneering strategies. Targeted drug delivery is an evolving frontier in cancer therapy, aiming enhance treatment efficacy while mitigating undesirable side effects. One promising avenue utilizes cell membrane receptors like folate receptor guide transporters precisely malignant cells. Based on cellular as hallmark, targeted nanocarriers and small molecule-drug conjugates have been developed that comprise different (bio) chemistries and/or mechanical properties with individual advantages challenges. Such modern folic acid-conjugated stimuli-responsive provide systemic controlled release, enabling reduced dosages, circumvention resistance, diminished adverse Since transporters' structure-based

Language: Английский

Citations

20
Galectin-1 fosters an immunosuppressive microenvironment in colorectal cancer by reprogramming CD8 + regulatory T cells DOI Open Access
Alejandro J. Cagnoni, María Laura Giribaldi, Ada G. Blidner

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 118(21)

Published: May 18, 2021

Significance Although immune checkpoint blockade therapies have achieved long-term responses in several malignancies, colorectal cancer (CRC) patients clinical benefit is observed only heavily mutated tumors that are mismatch-repair–deficient or high microsatellite instability. This limitation urges the identification of novel escape mechanisms and design additional immunotherapeutic modalities. We show Galectin-1 (Gal-1) confers privilege to CRC by increasing frequency CD8 + CD122 PD-1 regulatory T cells (Tregs) accentuating their immunosuppressive activity experimental models. Accordingly, analysis patient datasets revealed a “poor prognosis signature” characterized Gal-1 expression elevated Treg score. Thus, targeting Gal-1/glycan interactions may represent potential modality for treating recalibrating compartment.

Language: Английский

Citations

86
Plant lectin: A promising future anti-tumor drug DOI Creative Commons
Emadeldin Hassan E. Konozy, Makarim Elfadil M. Osman

Biochimie, Journal Year: 2022, Volume and Issue: 202, P. 136 - 145

Published: Aug. 8, 2022

Since the early discovery of plant lectins at end 19th century, and finding that they could agglutinate erythrocytes precipitate glycans from their solutions, many applications biological roles have been described for these proteins. Later, observed clumping features were attributed to lectin-cell surface glycoconjugates recognition. Neoplastic transformation leads various cellular alterations which impact growth cell its persistence, among is mutation in outer glycosylation signatures. Quite a few found act as excellent biomarkers cancer diagnosis while some presented with antiproliferative activity initiated by lectin binding respective glycocalyx receptors. These properties are blocked hapten sugar competing affinity site. In vitro investigations lectin-cancer cell's interactions lead series immunological reactions result autophagy or apoptosis transformed cells. Mistletoe lectin, an agglutinin purified European Viscum album first employed treatment enter into clinical trial phases. The entrapment nanoparticles besides other techniques promote bioavailability stability also recently studied. This review summarizes our up-to-date understanding future prognosis diagnosis. With provision examples exhibit anti-neoplastic properties.

Language: Английский

Citations

40
Precise Assembly of Proteins and Carbohydrates for Next-Generation Biomaterials DOI
Long Li, Guosong Chen

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(36), P. 16232 - 16251

Published: Aug. 31, 2022

The complexity and diversity of biomacromolecules make them a unique class building blocks for generating precise assemblies. They are particularly available to new generation biomaterials integrated with living systems due their intrinsic properties such as accurate recognition, self-organization, adaptability. Therefore, many excellent approaches have been developed, leading variety quite practical outcomes. Here, we review recent advances in the fabrication application artificially assemblies by employing proteins carbohydrates blocks, followed our perspectives on some challenges, goals, opportunities future research directions this field.

Language: Английский

Citations

39
Dissecting the Ability of Siglecs To Antagonize Fcγ Receptors DOI Creative Commons
Kelli A. McCord, Chao Wang,

Mirjam Anhalt

et al.

ACS Central Science, Journal Year: 2024, Volume and Issue: 10(2), P. 315 - 330

Published: Jan. 17, 2024

Fcγ receptors (FcγRs) play key roles in the effector function of IgG, but their inappropriate activation plays a role several disease etiologies. Therefore, it is critical to better understand how FcγRs are regulated. Numerous studies suggest that sialic acid-binding immunoglobulin-type lectins (Siglecs), family immunomodulatory receptors, modulate FcγR activity; however, unclear circumstances which Siglecs can antagonize and have this ability. Using liposomes displaying selective ligands coengage with specific Siglec, we explore ability Siglec-3, Siglec-5, Siglec-7, Siglec-9 signaling downstream FcγRs. We demonstrate Siglec-3 fully inhibit U937 cells when coengaged Cells expressing Siglec mutants reveal differential for tyrosine-based inhibitory motif (ITIM) switch (ITSM) inhibition. Imaging flow cytometry enabled visualization SHP-1 recruitment an ITIM-dependent manner, while SHP-2 more ITSM-dependent. Conversely, both cytosolic motifs contribute SHP-1/2 recruitment. Siglec-7 poorly antagonizes two reasons: masking by cis differences its ITIM ITSM. A chimera extracellular domains Siglec-5 tail strongly inhibits coengaged, providing evidence like Additionally, inhibited These results mediating inhibition context immunological synapse, has important relevance effectiveness immunotherapies.

Language: Английский

Citations

13
CAR T cells: Building on the CD19 paradigm DOI Open Access
Anat Globerson Levin,

Isabelle Rivière,

Zelig Eshhar

et al.

European Journal of Immunology, Journal Year: 2021, Volume and Issue: 51(9), P. 2151 - 2163

Published: July 2, 2021

Abstract Spearheaded by the therapeutic use of chimeric antigen receptors (CARs) targeting CD19, synthetic immunology has entered clinical arena. CARs are recombinant for that engage cell surface molecules through variable region an antibody and signal arrayed T‐cell activating costimulatory domains. allow redirection cytotoxicity against any choice, independent MHC expression. Patient T cells engineered to express specific CD19 have yielded remarkable outcomes in subjects with relapsed/refractory B‐ malignancies, setting off unprecedented interest engineering cell‐based cancer immunotherapy. In this review, we present challenges extend CAR solid tumors other pathologies. We further highlight progress design, manufacturing, genome editing, which aggregate hold promise generating safer more effective genetically instructed immunity. Novel types, including innate natural killer (NK) cells, macrophages, induced pluripotent stem cell‐derived immune on horizon, as applications treat autoimmunity, severe infections, senescence‐associated

Language: Английский

Citations

55
Disruption of the sialic acid/Siglec-9 axis improves antibody-mediated neutrophil cytotoxicity towards tumor cells DOI Creative Commons
Marta Lustig, Chilam Chan,

J.H. Marco Jansen

et al.

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

Published: June 6, 2023

Upregulation of surface expressed sialoglycans on tumor cells is one the mechanisms which promote growth and progression. Specifically, interactions sialic acids with acid-binding immunoglobulin-like lectins (Siglecs) lymphoid or myeloid transmit inhibitory signals lead to suppression anti-tumor responses. Here, we show that neutrophils express among others Siglec-9, EGFR HER2 positive breast ligands for Siglec-9. Treatment neuraminidases a sialyl transferase inhibitor significantly reduced binding soluble recombinant Siglec-9-Fc fusion protein, while expression remained unchanged. Importantly, cytotoxic activity driven by therapeutic antibodies in vitro was increased blocking acid/Siglec interaction, either reducing cell sialylation Siglec-9 antibody containing an effector silenced Fc domain. In vivo short-term xenograft mouse model confirmed improved efficacy against acid depleted, sialyltransferase inhibitor, compared untreated cells. Our studies demonstrate between can impair dependent killing, polymorphonuclear (PMN) critically involved. Considering PMN are often highly abundant population microenvironment, constitutes promising target checkpoint blockade improve antibody-based immunotherapy.

Language: Английский

Citations

19
Adoptive cell therapy for solid tumors beyond CAR-T: Current challenges and emerging therapeutic advances DOI
Tingrui Zhang, Zongguang Tai, Fengze Miao

et al.

Journal of Controlled Release, Journal Year: 2024, Volume and Issue: 368, P. 372 - 396

Published: March 6, 2024

Language: Английский

Citations

7
Exploring glycans as vital biological macromolecules: A comprehensive review of advancements in biomedical frontiers DOI
Kanika Arora,

P.M. Sherilraj,

K. A. Abutwaibe

et al.

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 268, P. 131511 - 131511

Published: April 13, 2024

Language: Английский

Citations

7