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Sainson, Richard C.A.; Thotakura, Anil K.; Kosmac, Miha; Borhis, Gwenoline; Parveen, Nahida; Kimber, Rachael; Carvalho, Joana; Henderson, Simon J.; Pryke, Kerstin L.; Okell, Tracey; O'Leary, Siobhan; Ball, Stuart; Van Krinks, Cassie; Gamand, Lauriane; Taggart, Emma; Pring, Eleanor J.; Ali, Hanif; Craig, Hannah; Wong, Vivian W.Y.; Liang, Qi; Rowlands, Robert J.; Lecointre, Morgane; Campbell, Jamie; Kirby, Ian; [...]

An Antibody Targeting ICOS Increases Intratumoral Cytotoxic to Regulatory T-cell Ratio and Induces Tumor Regression

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  • Medientyp: E-Artikel
  • Titel: An Antibody Targeting ICOS Increases Intratumoral Cytotoxic to Regulatory T-cell Ratio and Induces Tumor Regression
  • Beteiligte: Sainson, Richard C.A.; Thotakura, Anil K.; Kosmac, Miha; Borhis, Gwenoline; Parveen, Nahida; Kimber, Rachael; Carvalho, Joana; Henderson, Simon J.; Pryke, Kerstin L.; Okell, Tracey; O'Leary, Siobhan; Ball, Stuart; Van Krinks, Cassie; Gamand, Lauriane; Taggart, Emma; Pring, Eleanor J.; Ali, Hanif; Craig, Hannah; Wong, Vivian W.Y.; Liang, Qi; Rowlands, Robert J.; Lecointre, Morgane; Campbell, Jamie; Kirby, Ian; [...]
  • Erschienen: American Association for Cancer Research (AACR), 2020
  • Erschienen in: Cancer Immunology Research, 8 (2020) 12, Seite 1568-1582
  • Sprache: Englisch
  • DOI: 10.1158/2326-6066.cir-20-0034
  • ISSN: 2326-6066; 2326-6074
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: AbstractThe immunosuppressive tumor microenvironment constitutes a significant hurdle to immune checkpoint inhibitor responses. Both soluble factors and specialized immune cells, such as regulatory T cells (Treg), are key components of active intratumoral immunosuppression. Inducible costimulatory receptor (ICOS) can be highly expressed in the tumor microenvironment, especially on immunosuppressive Treg, suggesting that it represents a relevant target for preferential depletion of these cells. Here, we performed immune profiling of samples from tumor-bearing mice and patients with cancer to demonstrate differential expression of ICOS in immune T-cell subsets in different tissues. ICOS expression was higher on intratumoral Treg than on effector CD8 T cells. In addition, by immunizing an Icos knockout transgenic mouse line expressing antibodies with human variable domains, we selected a fully human IgG1 antibody called KY1044 that bound ICOS from different species. We showed that KY1044 induced sustained depletion of ICOShigh T cells but was also associated with increased secretion of proinflammatory cytokines from ICOSlow effector T cells (Teff). In syngeneic mouse tumor models, KY1044 depleted ICOShigh Treg and increased the intratumoral TEff:Treg ratio, resulting in increased secretion of IFNγ and TNFα by TEff cells. KY1044 demonstrated monotherapy antitumor efficacy and improved anti–PD-L1 efficacy. In summary, we demonstrated that using KY1044, one can exploit the differential expression of ICOS on T-cell subtypes to improve the intratumoral immune contexture and restore an antitumor immune response.
  • Zugangsstatus: Freier Zugang