Human CD4+ iNKT cell adoptive immunotherapy induces anti-tumour responses against CD1d-negative EBV-driven B lymphoma

Dana C Baiu; Akshat Sharma; Jennifer L Schehr; Jayati Basu; Kelsey A Smith; Makoto Ohashi; Eric C Johannsen; Shannon C Kenney; Jenny E Gumperz

doi:10.1111/imm.13799

Human CD4⁺ iNKT cell adoptive immunotherapy induces anti-tumour responses against CD1d-negative EBV-driven B lymphoma

Immunology. 2024 May 13. doi: 10.1111/imm.13799. Online ahead of print.

Authors

Dana C Baiu¹, Akshat Sharma¹, Jennifer L Schehr², Jayati Basu³, Kelsey A Smith¹, Makoto Ohashi⁴, Eric C Johannsen⁴, Shannon C Kenney⁴, Jenny E Gumperz¹

Affiliations

¹ Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
² Carbone Comprehensive Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
³ Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
⁴ Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.

PMID: 38736328
DOI: 10.1111/imm.13799

Abstract

Invariant natural killer T (iNKT) cells are a conserved population of innate T lymphocytes that are uniquely suitable as off-the-shelf cellular immunotherapies due to their lack of alloreactivity. Two major subpopulations of human iNKT cells have been delineated, a CD4^- subset that has a T_H1/cytolytic profile, and a CD4⁺ subset that appears polyfunctional and can produce both regulatory and immunostimulatory cytokines. Whether these two subsets differ in anti-tumour effects is not known. Using live cell imaging, we found that CD4^- iNKT cells limited growth of CD1d⁺ Epstein-Barr virus (EBV)-infected B-lymphoblastoid spheroids in vitro, whereas CD4⁺ iNKT cells showed little or no direct anti-tumour activity. However, the effects of the two subsets were reversed when we tested them as adoptive immunotherapies in vivo using a xenograft model of EBV-driven human B cell lymphoma. We found that EBV-infected B cells down-regulated CD1d in vivo, and administering CD4^- iNKT cells had no discernable impact on tumour mass. In contrast, xenotransplanted mice bearing lymphomas showed rapid reduction in tumour mass after administering CD4⁺ iNKT cells. Immunotherapeutic CD4⁺ iNKT cells trafficked to both spleen and tumour and were associated with subsequently enhanced responses of xenotransplanted human T cells against EBV. CD4⁺ iNKT cells also had adjuvant-like effects on monocyte-derived DCs and promoted antigen-dependent responses of human T cells in vitro. These results show that allogeneic CD4⁺ iNKT cellular immunotherapy leads to marked anti-tumour activity through indirect pathways that do not require tumour cell CD1d expression and that are associated with enhanced activity of antigen-specific T cells.

Keywords: CD1d; EBV; adjuvancy; iNKT cells; lymphoma; tumour immunotherapy.

Abstract

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