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Review
. 2023 May 13;24(10):8722.
doi: 10.3390/ijms24108722.

Butyrophilins: Dynamic Regulators of Protective T Cell Immunity in Cancer

Rinkee Kumari  1 , Elaheh Sadat Hosseini  1   2 , Kristen E Warrington  1 , Tyler Milonas  1 , Kyle K Payne  1   2   3
Affiliations
Review

Butyrophilins: Dynamic Regulators of Protective T Cell Immunity in Cancer

Rinkee Kumari et al. Int J Mol Sci. .

Abstract

The efficacy of current immunotherapies remains limited in many solid epithelial malignancies. Recent investigations into the biology of butyrophilin (BTN) and butyrophilin-like (BTNL) molecules, however, suggest these molecules are potent immunosuppressors of antigen-specific protective T cell activity in tumor beds. BTN and BTNL molecules also associate with each other dynamically on cellular surfaces in specific contexts, which modulates their biology. At least in the case of BTN3A1, this dynamism drives the immunosuppression of αβ T cells or the activation of Vγ9Vδ2 T cells. Clearly, there is much to learn regarding the biology of BTN and BTNL molecules in the context of cancer, where they may represent intriguing immunotherapeutic targets that could potentially synergize with the current class of immune modulators in cancer. Here, we discuss our current understanding of BTN and BTNL biology, with a particular focus on BTN3A1, and potential therapeutic implications for cancer.

Keywords: butyrophilins; immune oncology; immune suppression; immunotherapy; γδ T cells.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
BTN3A1 transformation from an immunosuppressive to an immunostimulatory molecule upon sensing pAgs or anti-BTN3A-specific antibodies. (A) BTN3A1 engagement with N-glycans of CD45 inhibits segregation of N-glycosylated CD45 from the immune synapse on the surface of αβ T cells and prevents the activation of the tumor-reactive T cells; (B) Anti-BTN3A antibodies or pAgs sensed by BTN3A1 drive BTN3A1:BTN2A1 interactions; BTN2A1 binds to the Vγ9 TCR chain and promotes Vγ9Vδ2 subset of γδ T cell activation. Transformation of BTN3A1 from an immunosuppressive molecule (through engagement with N-glycosylated CD45) for tumor antigen-specific T cells to an immunostimulatory molecule also rescues αβ T cell anti-tumor activity.
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