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

• Published in: Blood advances 2020-05, Vol.4 (10), p.2143-2157
• Main Authors: Manna, Alak, Kellett, Timothy, Aulakh, Sonikpreet, Lewis-Tuffin, Laura J., Dutta, Navnita, Knutson, Keith, Chini, Eduardo, Pinilla-Ibarz, Javier, Lamanna, Nicole, Manochakian, Rami, Malavasi, Fabio, Sher, Taimur, Chanan-Khan, Asher A., Ailawadhi, Sikander, Paulus, Aneel
• Format: Article
• Language: English
• Subjects: B-Lymphocytes, Regulatory; CD8-Positive T-Lymphocytes; Humans; Immunobiology and Immunotherapy; Immunosuppressive Agents; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; T-Lymphocytes, Regulatory; Tumor Microenvironment
• ISSN: 2473-9529; 2473-9537
• DOI: 10.1182/bloodadvances.2019001091

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. •CD38hi Breg-like CLL cells promote conversion of naive T cells into Tregs in an IL-10/TGF-β–dependent manner.•CD38 targeting drugs are lethal to both IL-10–producing Breg-like CLL cells and Tregs, but lead to improved CD8+ T-cell cytolytic responses. [Display omitted]