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J Immunol. 2018 Oct 1;201(7):1967-1974. doi: 10.4049/jimmunol.1800570. Epub 2018 Aug 13.

Activation of Th1 Immunity within the Tumor Microenvironment Is Associated with Clinical Response to Lenalidomide in Chronic Lymphocytic Leukemia.

Author information

1
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
2
Department of Medicine, The University of Chicago, Chicago, IL 60637.
3
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
4
Office of Biostatistics Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; and.
5
Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, MD 20892.
6
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; wiestnera@mail.nih.gov.

Abstract

Immune stimulation contributes to lenalidomide's antitumor activity. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature, autoreactive B cells in secondary lymphoid tissues, blood, and bone marrow and progressive immune dysfunction. Previous studies in CLL indicated that lenalidomide can repair defective T cell function in vitro. Whether T cell activation is required for clinical response to lenalidomide remains unclear. In this study, we report changes in the immune microenvironment in patients with CLL treated with single-agent lenalidomide and associate the immunologic effects of lenalidomide with antitumor response. Within days of starting lenalidomide, T cells increased in the tumor microenvironment and showed Th1-type polarization. Gene expression profiling of pretreatment and on-treatment lymph node biopsy specimens revealed upregulation of IFN-γ and many of its target genes in response to lenalidomide. The IFN-γ-mediated Th1 response was limited to patients achieving a clinical response defined by a reduction in lymphadenopathy. Deep sequencing of TCR genes revealed decreasing diversity of the T cell repertoire and an expansion of select clonotypes in responders. To validate our observations, we stimulated T cells and CLL cells with lenalidomide in culture and detected lenalidomide-dependent increases in T cell proliferation. Taken together, our data demonstrate that lenalidomide induced Th1 immunity in the lymph node that is associated with clinical response.

PMID:
30104242
PMCID:
PMC6143435
DOI:
10.4049/jimmunol.1800570
[Indexed for MEDLINE]
Free PMC Article

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