Targeting CD38 is lethal to Breg-like chronic lymphocytic leukemia cells and Tregs, but restores CD8+ T-cell responses

Abstract

Patients with chronic lymphocytic leukemia (CLL) are characterized by monoclonal expansion of CD5+CD23+CD27+CD19+κ/λ+ 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 CD19+CD24+CD38hi immunophenotype (B regulatory cell [Breg]–like CLL cells) produce high amounts of IL-10 and transforming growth factor β (TGF-β) and are capable of transforming naive T helper cells into CD4+CD25+FoxP3+ T regulatory cells (Tregs) in an IL-10/TGF-β-dependent manner. A strong correlation between the percentage of CD38+ CLL cells and Tregs was observed. CD38hi 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-γ and proliferation of cytotoxic CD8+ 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 PD1+CD38hiCD8+ T cells, but increased Th17 and CD8+ 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.

The Key Role of NAD+ in Anti-Tumor Immune Response: An Update

“…Indeed, recent studies have addressed the efficacy of CD38 inhibitors (i.e. kuromanin) in preclinical models of CLL (33,34) in combination with standard therapies. In addition, Nam has been administered in combination with radiotherapy or chemotherapy to patients with different solid tumors, obtaining promising effects (35).…”

Understanding the Immune-Stroma Microenvironment in B Cell Malignancies for Effective Immunotherapy

“…For example, cytokines within immune TMEs including IL-10 ( 131 ), IL-6 ( 132 ) and TGFβ ( 133 ) or extracellular vesicles (EVs) ( 134 , 135 ) are known to have complex, context-dependent effects on both immune and cancer cells. Although there is evidence that these secreted factors have relevant immunomodulatory activity in B cell malignancies including CLL ( 172 – 176 ) and FL ( 177 ), our understanding of the hierarchy and cooperation required between cytokines and chemokines or EVs and their cellular sources for the licensing of immune evasion or the promotion of anti-tumor immune responses is currently ill-defined.…”

Immune Dysfunctions and Immune-Based Therapeutic Interventions in Chronic Lymphocytic Leukemia

“…A number of studies attributed a prognostic value to the CD4:CD8 ratio, whose inversion has been associated with advanced disease, and has shown to predict a shorter time to first treatment and overall survival (82)(83)(84). Concerning Th subset distribution, most reports agree on the accumulation of Th1 T cells in the peripheral blood of CLL patients compared to healthy controls, whereas data on Th2 T cells are still controversial (85)(86)(87)(88). From the functional standpoint, a recent article by Roessner et al has investigated the pro-or anti-tumoral effect of Th1 T cells on CLL development, showing that the accumulation of Th1 T cells observed in human CLL and in a mice with CLL-like disease has no impact on disease progression (87).…”

“…Patients with CLL have an increased frequency and absolute number of Th17 cells, and higher IL-17A and IL-17F serum levels compared to healthy controls. Of note, the Th17-cell number is associated with the presence of favorable prognostic factors, an early stage of the disease and a longer overall survival (85,88,(128)(129)(130)(131)(132)(133). Although these evidences suggest that Th17 cells may have a protective function, their role within the CLL microenvironment is not yet fully understood.…”