دورية أكاديمية
أعرض في EDS

Fc-Optimized Anti-CCR8 Antibody Depletes Regulatory T Cells in Human Tumor Models.

التفاصيل البيبلوغرافية
العنوان: Fc-Optimized Anti-CCR8 Antibody Depletes Regulatory T Cells in Human Tumor Models.
المؤلفون: Campbell JR; Bristol Myers Squibb, Redwood City, California., McDonald BR; Bristol Myers Squibb, Redwood City, California., Mesko PB; Bristol Myers Squibb, Redwood City, California., Siemers NO; Bristol Myers Squibb, Redwood City, California., Singh PB; Bristol Myers Squibb, Redwood City, California., Selby M; Bristol Myers Squibb, Redwood City, California., Sproul TW; Bristol Myers Squibb, Redwood City, California., Korman AJ; Bristol Myers Squibb, Redwood City, California., Vlach LM; Bristol Myers Squibb, Redwood City, California., Houser J; Bristol Myers Squibb, Redwood City, California., Sambanthamoorthy S; Bristol Myers Squibb, Redwood City, California., Lu K; Bristol Myers Squibb, Redwood City, California., Hatcher SV; Bristol Myers Squibb, Redwood City, California., Lohre J; Bristol Myers Squibb, Redwood City, California., Jain R; Bristol Myers Squibb, Redwood City, California. ruth.lan321@gmail.com renujain429@gmail.com., Lan RY; Bristol Myers Squibb, Redwood City, California. ruth.lan321@gmail.com renujain429@gmail.com.
المصدر: Cancer research [Cancer Res] 2021 Jun 01; Vol. 81 (11), pp. 2983-2994. Date of Electronic Publication: 2021 Mar 23.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 2984705R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-7445 (Electronic) Linking ISSN: 00085472 NLM ISO Abbreviation: Cancer Res Subsets: MEDLINE
أسماء مطبوعة: Publication: Baltimore, Md. : American Association for Cancer Research
Original Publication: Chicago [etc.]
مواضيع طبية MeSH: Gene Expression Regulation, Neoplastic*, Antibodies, Monoclonal/*pharmacology , Immune Tolerance/*immunology , Immunoglobulin Fc Fragments/*immunology , Neoplasms/*immunology , Receptors, CCR8/*antagonists & inhibitors , T-Lymphocytes, Regulatory/*immunology, Animals ; Apoptosis ; Cell Proliferation ; Female ; Humans ; Immunotherapy/methods ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasms/pathology ; Neoplasms/therapy ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Programmed Cell Death 1 Receptor/immunology ; Receptors, CCR8/immunology ; Skin/drug effects ; Skin/immunology ; Skin/metabolism ; Skin/pathology ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
مستخلص: FOXP3 + regulatory T cells (Treg) play a critical role in mediating tolerance to self-antigens and can repress antitumor immunity through multiple mechanisms. Therefore, targeted depletion of tumor-resident Tregs is warranted to promote effective antitumor immunity while preserving peripheral homeostasis. Here, we propose the chemokine receptor CCR8 as one such optimal tumor Treg target. CCR8 was expressed by Tregs in both murine and human tumors, and unlike CCR4, a Treg depletion target in the clinic, CCR8 was selectively expressed on suppressive tumor Tregs and minimally expressed on proinflammatory effector T cells (T eff ). Preclinical mouse tumor modeling showed that depletion of CCR8 + Tregs through an FcyR-engaging anti-CCR8 antibody, but not blockade, enabled dose-dependent, effective, and long-lasting antitumor immunity that synergized with PD-1 blockade. This depletion was tumor Treg-restricted, sparing CCR8 + T cells in the spleen, thymus, and skin of mice. Importantly, Fc-optimized, nonfucosylated (nf) anti-human CCR8 antibodies specifically depleted Tregs and not T effs in ex vivo tumor cultures from primary human specimens. These findings suggest that anti-CCR8-nf antibodies may deliver optimal tumor-targeted Treg depletion in the clinic, providing long-term antitumor memory responses while limiting peripheral toxicities. SIGNIFICANCE: These findings show that selective depletion of regulatory T cells with an anti-CCR8 antibody can improve antitumor immune responses as a monotherapy or in combination with other immunotherapies. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/11/2983/F1.large.jpg.
(©2021 American Association for Cancer Research.)
التعليقات: Comment in: Cancer Res. 2021 Jun 1;81(11):2817-2819. (PMID: 34087782)
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المشرفين على المادة: 0 (Antibodies, Monoclonal)
0 (CCR8 protein, human)
0 (Immunoglobulin Fc Fragments)
0 (Programmed Cell Death 1 Receptor)
0 (Receptors, CCR8)
تواريخ الأحداث: Date Created: 20210324 Date Completed: 20211104 Latest Revision: 20211104
رمز التحديث: 20231215
DOI: 10.1158/0008-5472.CAN-20-3585
PMID: 33757978
قاعدة البيانات: MEDLINE
الوصف
تدمد:1538-7445
DOI:10.1158/0008-5472.CAN-20-3585