Invariant NKT cells contribute to chronic lymphocytic leukemia surveillance and prognosis

Abstract

Chronic lymphocytic leukemia (CLL) is characterized by the expansion of malignant CD5 B lymphocytes in blood, bone marrow, and lymphoid organs. CD1d-restricted invariant natural killer T (iNKT) cells are innate-like T lymphocytes strongly implicated in tumor surveillance. We investigated the impact of iNKT cells in the natural history of the disease in the Eμ-Tcl1 (Tcl1) CLL mouse model and 68 CLL patients. We found that Tcl1-CLL cells express CD1d and that iNKT cells critically delay disease onset but become functionally impaired upon disease progression. In patients, disease progression correlates with high CD1d expression on CLL cells and impaired iNKT cells. Conversely, disease stability correlates with negative or low CD1d expression on CLL cells and normal iNKT cells, suggesting indirect leukemia control. iNKT cells indeed hinder CLL survival in vitro by restraining CD1d-expressing nurse-like cells, a relevant proleukemia macrophage population. Multivariable analysis identified iNKT cell frequency as an independent predictor of disease progression. Together, these results support the contribution of iNKT cells to CLL immune surveillance and highlight iNKT cell frequency as a prognostic marker for disease progression.

The novel agonistic iNKT-cell antibody NKT14m induces a therapeutic antitumor response against B-cell lymphoma

“…In addition, iNKT-cell activation also inhibits tumor-induced myeloid derived suppressor cells (MDSCs) 8 and tumor angiogenesis 12 . Increased numbers of circulating and intra-tumor iNKT cells have been associated with an improved prognosis in different cancers and hematological malignancies, 13,14 supporting the important role of iNKT cells in cancer immunosurveillance and its potential as a promising immunotherapeutic target.…”

Natural Killer T Cells in Cancer Immunotherapy

“…Interestingly, in chronic lymphocytic leukemia (CLL), CD1d expression was found to increase during disease progression, counteracting the suggested role of CD1d as an anti-survival factor in cancer ( 102 , 103 ). However, a recent study has shown that higher CD1d expression on CLL cells associated with disease progression actually led to impairment in both function and numbers of type I NKT cells ( 104 ). CD1d independent cytotoxic effect of NKT cells on various hematopoietic tumor cell lines have also been reported ( 98 , 105 , 106 ).…”

Enhancement of Adjuvant Functions of Natural Killer T Cells Using Nanovector Delivery Systems: Application in Anticancer Immune Therapy

“…Unfortunately, no or low clinical benefits were reported among patients (22–24). These disappointing results might be due to the lower number of NKT cells in patients relative to healthy individuals and/or to their diminished (but reversible) activation threshold capacity (22–32). Hence, one concern in NKT cell-based therapy is the diminished NKT cell count and/or function, although this cannot be generalized to all advanced cancer patients.…”