ArticleJournal for immunotherapy of cancer2021
Paralysis of the cytotoxic granule machinery is a new cancer immune evasion mechanism mediated by chitinase 3-like-1.
Article in Journal for immunotherapy of cancer, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 19 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
19 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Natural Killer Cell-Derived Extracellular Vesicles as a Promising Immunotherapeutic Strategy for Cancer: A Systematic Review.International journal of molecular sciences · 2023Pooled it
- Plasma YKL-40 is associated with prognosis in patients with metastatic pancreatic cancer receiving immune checkpoint inhibitors in combination with radiotherapy.Frontiers in immunology · 2023Trial
- Redefining CHI3L1: Therapeutic Opportunities at the Crossroads of Immune Suppression and Disease Progression.Medicinal research reviews · 2026Review
- Characterization of ex vivo expanded natural killer cells for cancer immunotherapy.Immunology and cell biology · 2025Article
- Chitinase-3-like-1: a multifaceted player in neuroinflammation and degenerative pathologies with therapeutic implications.Molecular neurodegeneration · 2025Review
- Activated kynurenine pathway metabolism by YKL-40 establishes an inhibitory immune microenvironment and drives glioblastoma development.Cellular and molecular life sciences : CMLS · 2024Article
- Uncovering novel mechanisms of chitinase-3-like protein 1 in driving inflammation-associated cancers.Cancer cell international · 2024Review
- Proteomic Characterization of a 3D HER2+ Breast Cancer Model Reveals the Role of Mitochondrial Complex I in Acquired Resistance to Trastuzumab.International journal of molecular sciences · 2024Article
- Chitin-mediated blockade of chitinase-like proteins reduces tumor immunosuppression, inhibits lymphatic metastasis and enhances anti-PD-1 efficacy in complementary TNBC models.Breast cancer research : BCR · 2024Article
- A bibliometric analysis of drug resistance in immunotherapy for breast cancer: trends, themes, and research focus.Frontiers in immunology · 2024Article
- Cellular interactions in tumor microenvironment during breast cancer progression: new frontiers and implications for novel therapeutics.Frontiers in immunology · 2024Review
- Cancer stem cell-derived CHI3L1 activates the MAF/CTLA4 signaling pathway to promote immune escape in triple-negative breast cancer.Journal of translational medicine · 2023Article
- Antibody-drug conjugates come of age in oncology.Nature reviews. Drug discovery · 2023Review
- NKp46-specific single domain antibodies enable facile engineering of various potent NK cell engager formats.Protein science : a publication of the Protein Society · 2023Article
- Resistance to Trastuzumab.Cancers · 2022Review
- Chimeric antigen receptor T cells engineered to recognize the P329G-mutated Fc part of effector-silenced tumor antigen-targeting human IgG1 antibodies enable modular targeting of solid tumors.Journal for immunotherapy of cancer · 2022Article
- Focusing on NK cells and ADCC: A promising immunotherapy approach in targeted therapy for HER2-positive breast cancer.Frontiers in immunology · 2022Review
- Article
- Article
Corrections and comments
- Erratum issued
Authors and funding
17 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundNatural killer (NK) cells require a functional lytic granule machinery to mediate effective antitumor responses. Evading the lytic cargo deployed at the immune synapse (IS) could be a critical step for cancer progression through yet unidentified mechanisms.
methodsNK cell antibody-dependent cellular cytotoxicity (ADCC) is a major determinant of the clinical efficacy of some therapeutic antibodies including the anti-HER2 Trastuzumab. Thus, we screened sera of Trastuzumab-resistant HER2 +patients with breast cancer for molecules that could inhibit NK cell ADCC. We validated our findings in vitro using cytotoxicity assays and confocal imaging of the lytic granule machinery and in vivo using syngeneic and xenograft murine models.
resultsWe found that sera from Trastuzumab-refractory patients could inhibit healthy NK cell ADCC in vitro. These sera contained high levels of the inflammatory protein chitinase 3-like 1 (CHI3L1) compared with sera from responders and healthy controls. We demonstrate that recombinant CHI3L1 inhibits both ADCC and innate NK cell cytotoxicity. Mechanistically, CHI3L1 prevents the correct polarization of the microtubule-organizing center along with the lytic granules to the IS by hindering the receptor of advanced glycation end-products and its downstream JNK signaling. In vivo, CHI3L1 administration drastically impairs the control of NK cell-sensitive tumors, while CHI3L1 blockade synergizes with ADCC to cure mice with HER2 +xenografts.
conclusionOur work highlights a new paradigm of tumor immune escape mediated by CHI3L1 which acts on the cytotoxic machinery and prevents granule polarization. Targeting CHI3L1 could mitigate immune escape and potentiate antibody and cell-based immunotherapies.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.