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

Autor: Sainson RCA; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom. richard.sainson@kymab.com., Thotakura AK; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom., Kosmac M; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom., Borhis G; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom., Parveen N; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom., Kimber R; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom., Carvalho J; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom., Henderson SJ; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom., Pryke KL; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom., Okell T; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom., O'Leary S; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom., Ball S; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom., Van Krinks C; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom., Gamand L; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom., Taggart E; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom., Pring EJ; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom., Ali H; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom., Craig H; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom., Wong VWY; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom., Liang Q; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom., Rowlands RJ; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom., Lecointre M; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom., Campbell J; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom., Kirby I; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom., Melvin D; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom., Germaschewski V; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom., Oelmann E; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom., Quaratino S; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom., McCourt M; Kymab Ltd, Babraham Research Campus, Cambridge, United Kingdom.
Jazyk: angličtina
Zdroj: Cancer immunology research [Cancer Immunol Res] 2020 Dec; Vol. 8 (12), pp. 1568-1582. Date of Electronic Publication: 2020 Sep 30.
DOI: 10.1158/2326-6066.CIR-20-0034
Abstrakt: The 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 ICOS high T cells but was also associated with increased secretion of proinflammatory cytokines from ICOS low effector T cells (T eff ). In syngeneic mouse tumor models, KY1044 depleted ICOS high Treg and increased the intratumoral T Eff :Treg ratio, resulting in increased secretion of IFNγ and TNFα by T Eff 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.
(©2020 American Association for Cancer Research.)
Databáze: MEDLINE
Externí odkaz: