Targeting CD38 is lethal to Breg-like chronic lymphocytic leukemia cells and Tregs, but restores CD8¹ T-cell responses

Patients with chronic lymphocytic leukemia (CLL) are characterized by monoclonal expansion of CD5¹CD23¹CD27¹CD19¹k/l¹ B lymphocytes and are clinically noted to have profound immune suppression. In these patients, it has been recently shown that a subset of B cells possesses regulatory functions and secretes high levels of interleukin 10 (IL-10). Our investigation identified that CLL cells with a CD19¹CD24¹CD38^hi immunophenotype (B regulatory cell [Breg]-like CLL cells) produce high amounts of IL-10 and transforming growth factor b (TGF-b) and are capable of transforming naive T helper cells into CD4¹ CD25¹FoxP3¹ T regulatory cells (Tregs) in an IL-10/TGF-b-dependent manner. A strong correlation between the percentage of CD38¹ CLL cells and Tregs was observed. CD38^hi Tregs comprised more than 50% of Tregs in peripheral blood mononuclear cells (PBMCs) in patients with CLL. Anti-CD38 targeting agents resulted in lethality of both Breg-like CLL and Treg cells via apoptosis. Ex vivo, use of anti-CD38 monoclonal antibody (mAb) therapy was associated with a reduction in IL-10 and CLL patient-derived Tregs, but an increase in interferon-g and proliferation of cytotoxic CD8¹ T cells with an activated phenotype, which showed an improved ability to lyse patient-autologous CLL cells. Finally, effects of anti-CD38 mAb therapy were validated in a CLL-patient-derived xenograft model in vivo, which showed decreased percentage of Bregs, Tregs, and PD1¹CD38^hiCD8¹ T cells, but increased Th17 and CD8¹ T cells (vs vehicle). Altogether, our results demonstrate that targeting CD38 in CLL can modulate the tumor microenvironment; skewing T-cell populations from an immunosuppressive to immune-reactive milieu, thus promoting immune reconstitution for enhanced anti-CLL response.