人 CD4(+) iNKT 细胞过继免疫治疗诱导针对 CD1d 阴性 EBV 驱动 B 淋巴瘤的抗肿瘤反应

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.