Your browser doesn't support javascript.
loading
PD-1 or CTLA-4 blockade promotes CD86-driven Treg responses upon radiotherapy of lymphocyte-depleted cancer in mice.
Frijlink, Elselien; Bosma, Douwe Mt; Busselaar, Julia; Battaglia, Thomas W; Staal, Mo D; Verbrugge, Inge; Borst, Jannie.
Affiliation
  • Frijlink E; Division of Tumor Biology and Immunology and Oncode Institute, The Netherlands Cancer Institute, Amsterdam, Netherlands.
  • Bosma DM; Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, Netherlands.
  • Busselaar J; Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, Netherlands.
  • Battaglia TW; Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, Netherlands.
  • Staal MD; Division of Molecular Oncology and Immunology and Oncode Institute, The Netherlands Cancer Institute, Amsterdam, Netherlands.
  • Verbrugge I; Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, Netherlands.
  • Borst J; Division of Tumor Biology and Immunology and Oncode Institute, The Netherlands Cancer Institute, Amsterdam, Netherlands.
J Clin Invest ; 134(6)2024 Feb 13.
Article in En | MEDLINE | ID: mdl-38349740
ABSTRACT
Radiotherapy (RT) is considered immunogenic, but clinical data demonstrating RT-induced T cell priming are scarce. Here, we show in a mouse tumor model representative of human lymphocyte-depleted cancer that RT enhanced spontaneous priming of thymus-derived (FOXP3+Helios+) Tregs by the tumor. These Tregs acquired an effector phenotype, populated the tumor, and impeded tumor control by a simultaneous, RT-induced CD8+ cytotoxic T cell (CTL) response. Combination of RT with CTLA-4 or PD-1 blockade, which enables CD28 costimulation, further increased this Treg response and failed to improve tumor control. We discovered that upon RT, the CD28 ligands CD86 and CD80 differentially affected the Treg response. CD86, but not CD80, blockade prevented the effector Treg response, enriched the tumor-draining lymph node migratory conventional DCs that were positive for PD-L1 and CD80 (PD-L1+CD80+), and promoted CTL priming. Blockade of CD86 alone or in combination with PD-1 enhanced intratumoral CTL accumulation, and the combination significantly increased RT-induced tumor regression and OS. We advise that combining RT with PD-1 and/or CTLA-4 blockade may be counterproductive in lymphocyte-depleted cancers, since these interventions drive Treg responses in this context. However, combining RT with CD86 blockade may promote the control of such tumors by enabling a CTL response.
Subject(s)
Key words

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: CD28 Antigens / Neoplasms Limits: Animals / Humans Language: En Journal: J Clin Invest Year: 2024 Document type: Article Affiliation country: Country of publication:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: CD28 Antigens / Neoplasms Limits: Animals / Humans Language: En Journal: J Clin Invest Year: 2024 Document type: Article Affiliation country: Country of publication: