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LILRB1 blockade enhances bispecific T cell engager antibody-induced tumor cell killing by effector CD8+ T cells

Kim, Aeryon, Han, Chia-Jung, Driver, Ian, Olow, Aleksandra, Sewell, Andrew K., Zhang, Zemin, Ouyang, Wenjun, Egen, Jackson G. and Yu, Xin 2019. LILRB1 blockade enhances bispecific T cell engager antibody-induced tumor cell killing by effector CD8+ T cells. Journal of Immunology 203 (4) , pp. 1076-1087. 10.4049/jimmunol.1801472

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Abstract

Elicitation of tumor cell killing by CD8+ T cells is an effective therapeutic approach for cancer. In addition to using immune checkpoint blockade to reinvigorate existing but unresponsive tumor-specific T cells, alternative therapeutic approaches have been developed, including stimulation of polyclonal T cell cytolytic activity against tumors using bispecific T cell engager (BiTE) molecules that simultaneously engage the TCR complex and a tumor-associated Ag. BiTE molecules are efficacious against hematologic tumors and are currently being explored as an immunotherapy for solid tumors. To understand mechanisms regulating BiTE molecule­–mediated CD8+ T cell activity against solid tumors, we sought to define human CD8+ T cell populations that efficiently respond to BiTE molecule stimulation and identify factors regulating their cytolytic activity. We find that human CD45RA+CCR7− CD8+ T cells are highly responsive to BiTE molecule stimulation, are enriched in genes associated with cytolytic effector function, and express multiple unique inhibitory receptors, including leukocyte Ig-like receptor B1 (LILRB1). LILRB1 and programmed cell death protein 1 (PD1) were found to be expressed by distinct CD8+ T cell populations, suggesting different roles in regulating the antitumor response. Engaging LILRB1 with its ligand HLA-G on tumor cells significantly inhibited BiTE molecule–induced CD8+ T cell activation. Blockades of LILRB1 and PD1 induced greater CD8+ T cell activation than either treatment alone. Together, our data suggest that LILRB1 functions as a negative regulator of human CD8+ effector T cells and that blocking LILRB1 represents a unique strategy to enhance BiTE molecule therapeutic activity against solid tumors.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: Freely available online through The Journal of Immunology Author Choice option
Publisher: American Association of Immunologists
ISSN: 0022-1767
Date of First Compliant Deposit: 19 November 2019
Date of Acceptance: 10 June 2019
Last Modified: 19 Nov 2019 17:15
URI: http://orca-mwe.cf.ac.uk/id/eprint/124463

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