Modulation of immune checkpoint molecule expression in mantle cell lymphoma

Abstract

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy for which novel therapeutics with improved efficacy are greatly needed. To provide support for clinical immune checkpoint blockade, we comprehensively evaluated the expression of therapeutically targetable immune checkpoint molecules on primary MCL cells. MCL cells showed constitutive expression of Programmed Death 1 (PD-1) and Programmed Death Ligand 1 (PD-L1), variable CD200, absent PD-L2, Lymphocyte Activation Gene 3 (LAG-3), and Cytotoxic T-cell Associated Protein 4 (CTLA-4). Effector cells from MCL patients expressed PD-1. Co-culture of MCL cells with T-cells induced PD-L1 surface expression, a phenomenon regulated by IFNγ and CD40:CD40L interaction. Induction of PD-L1 was attenuated by concurrent treatment with ibrutinib or duvelisib, suggesting BTK and PI3K are important mediators of PD-L1 expression. Overall, our data provide further insight into the expression of checkpoint molecules in MCL and support the use of PD-L1 blocking antibodies in MCL patients.

Keywords:

• Mantle cell lymphoma
• immune checkpoint molecules
• PD-L1
• PD-L2
• CTLA-4
• LAG3
• PD-1
• CD200

Acknowledgments

We would like to acknowledge Yuh-Ying Yeh for her contributions toward the validation of methodologies used in the manuscript.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article online at https://doi.org/10.1080/10428194.2019.1569231.

Additional information

Funding

This was supported the NIH NCI under the Oncology T32 Training Grant T32CA009338 (B.K.H), the CLL Research Consortium (CRC) P01 CA081534, and the OSU Comprehensive Cancer Center Support Grant P30 CA016058. This work was also supported by the Pelotonia Graduate Fellowship (B.K.H.), the CCTS Davis-Bremer Scholar Award (L.A.), and the D. Warren Brown Foundation.