Combinatorial blockade for cancer immunotherapy: targeting emerging immune checkpoint receptors

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

Published: Oct. 19, 2023

The differentiation, survival, and effector function of tumor-specific CD8 + cytotoxic T cells lie at the center antitumor immunity. Due to lack proper costimulation abundant immunosuppressive mechanisms, show a persistence exhausted dysfunctional phenotypes. Multiple coinhibitory receptors, such as PD-1, CTLA-4, VISTA, TIGIT, TIM-3, LAG-3, contribute CTLs failed These receptors are collectively called immune checkpoint (ICRs). Immune inhibitors (ICIs) targeting these ICRs have become cornerstone for cancer immunotherapy they established new clinical paradigms an expanding range previously untreatable cancers. Given nonredundant yet convergent molecular pathways mediated by various ICRs, combinatorial immunotherapies being tested bring synergistic benefits patients. In this review, we summarize mechanisms several emerging including preclinical data supporting strategies improve existing ICI therapies.

Language: Английский

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TIGIT can inhibit T cell activation via ligation-induced nanoclusters, independent of CD226 co-stimulation

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

Published: Aug. 18, 2023

Abstract TIGIT is an inhibitory receptor expressed on lymphocytes and can inhibit T cells by preventing CD226 co-stimulation through interactions in cis or competition of shared ligands. Whether directly delivers cell-intrinsic signals remains unclear. Here we show, analysing from matched human tumour peripheral blood samples, that co-expression rare tumour-infiltrating lymphocytes. Using super-resolution microscopy other techniques, demonstrate ligation with CD155 causes to reorganise into dense nanoclusters, which coalesce cell (TCR)-rich clusters at immune synapses. Functionally, this reduces cytokine secretion a manner dependent TIGIT’s intracellular ITT-like signalling motif. Thus, provide evidence inhibits lymphocyte activation, acting independently CD226, requiring proximal the TCR. Within subset tumours where TIGIT-expressing do not commonly co-express will likely be dominant mechanism action.

Language: Английский

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Blocking CD226 regulates type 2 innate lymphoid cell effector function and alleviates airway hyperreactivity

Journal of Allergy and Clinical Immunology, Journal Year: 2024, Volume and Issue: 153(5), P. 1406 - 1422.e6

Published: Jan. 19, 2024

Language: Английский

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A non-comparative, randomized, phase II trial of atezolizumab or atezolizumab plus tiragolumab for programmed death-ligand 1-positive recurrent cervical cancer (SKYSCRAPER-04)

International Journal of Gynecological Cancer, Journal Year: 2024, Volume and Issue: 34(8), P. 1140 - 1148

Published: June 11, 2024

Objective

To evaluate tiragolumab (anti-TIGIT) and atezolizumab (anti-PD-L1) as second- or third-line therapy for PD-L1-positive persistent/recurrent cervical cancer.

Methods

In the open-label, non-comparative, randomized phase II SKYSCRAPER-04 trial (NCT04300647), patients with (SP263 tumor area positivity ≥5%) recurrent/persistent cancer after 1–2 chemotherapy lines (≥1 platinum-based) were 3:1 to 1200 mg with/without 600 every 3 weeks until disease progression unacceptable toxicity. Stratification factors performance status, prior (chemo)radiotherapy, status. The primary endpoint was independent review committee-assessed confirmed objective response rate per RECIST v1.1 in receiving plus atezolizumab. An ≥21% (one-sample z-test p≤0.0245) required statistical significance versus a historical reference.

Results

Protocol-defined rates 19.0% (95% CI 12.6 27.0) 126 (p=0.0787 vs reference) 15.6% 6.5 29.5) 45 atezolizumab-treated patients. Response higher PD-L1_high (tumor ≥10%) than PD-L1_low 5%–9%) subgroups both regimens. At 8.5 months' median follow-up, progression-free survival 2.8 months 1.7 4.1) 1.9 1.5 3.0) post hoc analyses (10.4 follow-up), overall 11.1 9.6 14.5) combination 10.6 6.9 13.8) (crossover permitted). group, 3% of had adverse events requiring treatment discontinuation 8% grade ≥3 special interest; corresponding values single-agent arm 4% 11%. There no treatment-related deaths new safety findings.

Conclusion

tiragolumab-plus-atezolizumab numerically reference but did not reach significance.

Language: Английский

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Hemin blocks TIGIT/PVR interaction and induces ferroptosis to elicit synergistic effects of cancer immunotherapy

Science China Life Sciences, Journal Year: 2024, Volume and Issue: 67(5), P. 996 - 1009

Published: Feb. 1, 2024

Language: Английский

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A Novel Epigenetic Strategy to Concurrently Block Immune Checkpoints PD-1/PD-L1 and CD155/TIGIT in Hepatocellular Carcinoma

Translational Oncology, Journal Year: 2024, Volume and Issue: 45, P. 101961 - 101961

Published: April 17, 2024

Tumor microenvironment is an intricate web of stromal and immune cells creating suppressive cordon around the tumor. In hepatocellular carcinoma (HCC), a formidable barrier towards novel therapeutic approaches recently evading oncology field. this study, main aim was to identify evasion tactics mediated by HCC study epigenetic modulation checkpoints; Programmed death-1 (PD-1)/ death-Ligand 1 (PD-L1) T cell immunoreceptor with Ig ITIM domains (TIGIT)/Cluster Differentiation 155 (CD155) at tumor-immune synapse. Thus, liver tissues, PBMCs sera were collected from Hepatitis C Virus (HCV), as well healthy individuals. Screening performed PD-L1/PD-1 CD155/TIGIT axes in patients. PDL1, CD155, PD-1 TIGIT found be significantly upregulated tissues peripheral blood mononuclear (PBMCs) An array long non-coding RNAs (lncRNAs) microRNAs validated regulate such checkpoints screened. The lncRNAs; CCAT-1, H19, MALAT-1 all sera, PBMCs, patients compared HCV controls. However, miR-944-5p, miR-105-5p, miR-486-5p, miR-506-5p, miR-30a-5p downregulated On tumor side, knocking down lncRNAs-CCAT-1, MALAT-1, or H19-markedly repressed co-expression PD-L1 CD155 accordingly induced cytotoxicity co-cultured primary cells. ectopic expression under-expressed microRNAs; decreased transcript levels no effect on TIGIT. other hand, miR-944-5p miR-105-5p dramatically reduced Finally, studied miRNAs enhanced cytotoxic effects against Huh7 showed highest augmentation for conclusion, highlights co-targeting strategy using mimics, CCAT-1 H19 siRNAs efficiently hampers properties HCC.

Language: Английский

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Inhibitors of Immune Checkpoints: Small Molecule- and Peptide-Based Approaches

Journal of Personalized Medicine, Journal Year: 2024, Volume and Issue: 14(1), P. 68 - 68

Published: Jan. 4, 2024

The revolutionary progress in cancer immunotherapy, particularly the advent of immune checkpoint inhibitors, marks a significant milestone fight against malignancies. However, majority clinically employed inhibitors are monoclonal antibodies (mAbs) with several limitations, such as poor oral bioavailability and immune-related adverse effects (irAEs). Another major limitation is restriction efficacy mAbs to subset patients, which triggered extensive research efforts identify alternative approaches targeting checkpoints aiming overcome restricted mAbs. This comprehensive review aims explore cutting-edge developments checkpoints, focusing on both small molecule- peptide-based approaches. By delving into drug discovery platforms, we provide insights diverse strategies optimize molecules peptides checkpoints. In addition, discuss recent advances nanomaterials carriers, providing basis for development platforms immunotherapy. Ongoing focused peptide-inspired agents paves way developing orally bioavailable next-generation immunotherapies.

Language: Английский

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Increased TIGIT expression correlates with impaired NK cell function in diffuse large B-cell lymphoma

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 15

Published: March 31, 2025

This study aims to investigate the status of natural killer (NK) cells and role T-cell immunoreceptor with Ig ITIM domains (TIGIT)-mediated regulation in diffuse large B-cell lymphoma (DLBCL). Peripheral blood samples from 30 newly diagnosed DLBCL patients 25 healthy controls were collected. Multiparametric flow cytometry was used analyze expression levels TIGIT its family molecules (CD226 CD96) on NK cells, as well assess cell phenotype function. The restorative effects blockade cytotoxicity evaluated through vitro functional assays vivo animal models. Compared controls, exhibited significantly reduced percentages absolute numbers cells. markedly upregulated patients, while CD226 downregulated; however, no significant difference CD96 observed. These alterations associated impaired function including secretion activation factors such granzyme B, perforin, CD107a. Importantly, enhanced cytotoxic activity against both settings. Dysregulated contributes dysfunction promotes tumor immune escape DLBCL. findings highlight a promising therapeutic target for restoring cell-mediated antitumor immunity

Language: Английский

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Oncolytic viruses combined with immune checkpoint therapy for colorectal cancer is a promising treatment option

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: July 15, 2022

Immunotherapy is one of the promising strategies in treatment oncology. Immune checkpoint inhibitors, as a type immunotherapy, have no significant efficacy clinical patients with pMMR/MSS/MSI-L mCRC alone. Therefore, there an urgent need to find combination therapies that can improve response rate immune inhibitors. Oncolytic viruses are new class cancer drugs that, addition directly lysing tumor cells, facilitate action inhibitors by modulating microenvironment and transforming “cold” tumors into “hot” ones. The oncolytic currently being used several primary studies treat exciting results. genetically modified “armed” OV ICIs expected be options for mCRC. In this paper, we will analyze current status available CRC. feasibility ICI CRC discussed terms mechanism treating tumors.

Language: Английский

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TIGIT Expression on Activated NK Cells Correlates with Greater Anti-Tumor Activity but Promotes Functional Decline upon Lung Cancer Exposure: Implications for Adoptive Cell Therapy and TIGIT-Targeted Therapies

Cancers, Journal Year: 2023, Volume and Issue: 15(10), P. 2712 - 2712

Published: May 11, 2023

Treatments targeting TIGIT have gained a lot of attention due to strong preclinical and early clinical results, particularly with anti-PD-(L)1 therapeutics. However, this combination has failed meet progression-free survival endpoints in phase III trials. Most our understanding comes from studies T cell function. Yet, inhibitory receptor is often upregulated the same, or higher, extent on NK cells cancers. Studies murine models demonstrated that inhibits promotes exhaustion, its effects tumor control also being dependent cells. there are limited assessing role function human (hNK), lung cancer. used lines tested blockade reactivate exhausted obtained cancer patients. For therapeutic advancement, better context activated hNK crucial, which different than cells, critical adoptive therapeutics may be combined blockade. In study, effect anti-tumor activities ex vivo-expanded was evaluated vitro expression higher and/or expanded compared resting More

Language: Английский

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