Dataset Information

B7-H3×4-1BB bispecific antibody augments antitumor immunity by enhancing terminally differentiated CD8⁺ tumor-infiltrating lymphocytes.

ABSTRACT: Cancer immunotherapy with 4-1BB agonists has limited further clinical development because of dose-limiting toxicity. Here, we developed a bispecific antibody (bsAb; B7-H3×4-1BB), targeting human B7-H3 (hB7-H3) and mouse or human 4-1BB, to restrict the 4-1BB stimulation in tumors. B7-H3×m4-1BB elicited a 4-1BB-dependent antitumor response in hB7-H3-overexpressing tumor models without systemic toxicity. BsAb primarily targets CD8 T cells in the tumor and increases their proliferation and cytokine production. Among the CD8 T cell population in the tumor, 4-1BB is solely expressed on PD-1⁺Tim-3⁺ "terminally differentiated" subset, and bsAb potentiates these cells for eliminating the tumor. Furthermore, the combination of bsAb and PD-1 blockade synergistically inhibits tumor growth accompanied by further increasing terminally differentiated CD8 T cells. B7-H3×h4-1BB also shows antitumor activity in h4-1BB-expressing mice. Our data suggest that B7-H3×4-1BB is an effective and safe therapeutic agent against B7-H3-positive cancers as monotherapy and combination therapy with PD-1 blockade.

SUBMITTER: You G

PROVIDER: S-EPMC7810375 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

B7-H3×4-1BB bispecific antibody augments antitumor immunity by enhancing terminally differentiated CD8<sup>+</sup> tumor-infiltrating lymphocytes.

You Gihoon G Lee Yangsoon Y Kang Yeon-Woo YW Park Han Wook HW Park Kyeongsu K Kim Hyekang H Kim Young-Min YM Kim Sora S Kim Ji-Hae JH Moon Dain D Chung Hyejin H Son Wonjun W Jung Ui-Jung UJ Park Eunyoung E Lee Shinai S Son Yong-Gyu YG Eom Jaehyun J Won Jonghwa J Park Yunji Y Jung Jaeho J Lee Seung-Woo SW

Science advances 20210115 3

Cancer immunotherapy with 4-1BB agonists has limited further clinical development because of dose-limiting toxicity. Here, we developed a bispecific antibody (bsAb; B7-H3×4-1BB), targeting human B7-H3 (hB7-H3) and mouse or human 4-1BB, to restrict the 4-1BB stimulation in tumors. B7-H3×m4-1BB elicited a 4-1BB-dependent antitumor response in hB7-H3-overexpressing tumor models without systemic toxicity. BsAb primarily targets CD8 T cells in the tumor and increases their proliferation and cytokine ...[more]

PMID: 33523913

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Project description:The cardiovascular and immune systems undergo profound and intertwined alterations with aging. Recent studies have reported that an accumulation of memory and terminally differentiated T cells in elderly subjects can fuel myocardial aging and boost the progression of heart diseases. Nevertheless, it remains unclear whether the immunological senescence profile is sufficient to cause age-related cardiac deterioration or merely acts as an amplifier of previous tissue-intrinsic damage. Herein, we sought to decompose the causality in this cardio-immune crosstalk by studying young mice harboring a senescent-like expanded CD4+ T cell compartment. Thus, immunodeficient NSG-DR1 mice expressing HLA-DRB1*01:01 were transplanted with human CD4+ T cells purified from matching donors that rapidly engrafted and expanded in the recipients without causing xenograft reactions. In the donor subjects, the CD4+ T cell compartment was primarily composed of naïve cells defined as CCR7+CD45RO-. However, when transplanted into young lymphocyte-deficient mice, CD4+ T cells underwent homeostatic expansion, upregulated expression of PD-1 receptor and strongly shifted towards effector/memory (CCR7- CD45RO+) and terminally-differentiated phenotypes (CCR7-CD45RO-), as typically seen in elderly. Differentiated CD4+ T cells also infiltrated the myocardium of recipient mice at comparable levels to what is observed during physiological aging. In addition, young mice harboring an expanded CD4+ T cell compartment showed increased numbers of infiltrating monocytes, macrophages and dendritic cells in the heart. Bulk mRNA sequencing analyses further confirmed that expanding T-cells promote myocardial inflammaging, marked by a distinct age-related transcriptomic signature. Altogether, these data indicate that exaggerated CD4+ T-cell expansion and differentiation, a hallmark of the aging immune system, is sufficient to promote myocardial alterations compatible with inflammaging in juvenile healthy mice.

Dataset Information

B7-H3×4-1BB bispecific antibody augments antitumor immunity by enhancing terminally differentiated CD8⁺ tumor-infiltrating lymphocytes.

Publications

B7-H3×4-1BB bispecific antibody augments antitumor immunity by enhancing terminally differentiated CD8<sup>+</sup> tumor-infiltrating lymphocytes.

Similar Datasets

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Dataset Information

B7-H3×4-1BB bispecific antibody augments antitumor immunity by enhancing terminally differentiated CD8+ tumor-infiltrating lymphocytes.

Publications

B7-H3×4-1BB bispecific antibody augments antitumor immunity by enhancing terminally differentiated CD8<sup>+</sup> tumor-infiltrating lymphocytes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

B7-H3×4-1BB bispecific antibody augments antitumor immunity by enhancing terminally differentiated CD8⁺ tumor-infiltrating lymphocytes.