BiTE molecules are being investigated in solid tumor trials but the regulation of their activity is unclear. Kim et al. identified an effector memory subpopulation of CD8+ T cells from PBMCs and human tumors that expressed high levels of cytolytic molecules and was highly potent when combined with a BiTE. These CD45RA+CCR7- TEMRA cells expressed leukocyte Ig-like receptor B1 (LILRB1) that acts as a negative regulator of BiTE function. PD-1 and LILRB1 were independently expressed on different CD8+ populations and blocking both synergistically increased CD8+ T cell function. Blockade of LILRB1 may specifically enhance BiTE therapy.
Contributed by Katherine Turner
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.