RT Journal Article
SR Electronic
T1 An Antibody Targeting ICOS Increases Intratumoral Cytotoxic to Regulatory T-cell Ratio and Induces Tumor Regression
JF Cancer Immunology Research
JO Cancer Immunol Res
FD American Association for Cancer Research
SP 1568
OP 1582
DO 10.1158/2326-6066.CIR-20-0034
VO 8
IS 12
A1 Sainson, Richard C.A.
A1 Thotakura, Anil K.
A1 Kosmac, Miha
A1 Borhis, Gwenoline
A1 Parveen, Nahida
A1 Kimber, Rachael
A1 Carvalho, Joana
A1 Henderson, Simon J.
A1 Pryke, Kerstin L.
A1 Okell, Tracey
A1 O'Leary, Siobhan
A1 Ball, Stuart
A1 Van Krinks, Cassie
A1 Gamand, Lauriane
A1 Taggart, Emma
A1 Pring, Eleanor J.
A1 Ali, Hanif
A1 Craig, Hannah
A1 Wong, Vivian W.Y.
A1 Liang, Qi
A1 Rowlands, Robert J.
A1 Lecointre, Morgane
A1 Campbell, Jamie
A1 Kirby, Ian
A1 Melvin, David
A1 Germaschewski, Volker
A1 Oelmann, Elisabeth
A1 Quaratino, Sonia
A1 McCourt, Matthew
YR 2020
UL http://cancerimmunolres.aacrjournals.org/content/8/12/1568.abstract
AB 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 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.