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

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...

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Published in:Cancer immunology research 2020-12, Vol.8 (12), p.1568-1582
Main Authors: 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, Melvin, David, Germaschewski, Volker, Oelmann, Elisabeth, Quaratino, Sonia, McCourt, Matthew
Format: Article
Language:English
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Summary: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 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 T cells but was also associated with increased secretion of proinflammatory cytokines from ICOS effector T cells (T ). In syngeneic mouse tumor models, KY1044 depleted ICOS Treg and increased the intratumoral T :Treg ratio, resulting in increased secretion of IFNγ and TNFα by T 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.
ISSN:2326-6066
2326-6074
DOI:10.1158/2326-6066.CIR-20-0034