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

Alak Manna, Timothy Kellett, Sonikpreet Aulakh, Laura J. Lewis-Tuffin, Navnita Dutta, Keith Knutson, Eduardo Chini, Javier Pinilla-Ibarz, Nicole Lamanna, Rami Manochakian, Fabio Malavasi, Taimur Sher, Asher A. Chanan-Khan, Sikander Ailawadhi, Aneel Paulus

Research output: Contribution to journalArticle

Abstract

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 CD191CD241CD38hi 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. 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-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 PD11CD38hiCD81 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.

Original languageEnglish (US)
Pages (from-to)2143-2157
Number of pages15
JournalBlood Advances
Volume4
Issue number10
DOIs
StatePublished - May 26 2020

ASJC Scopus subject areas

  • Hematology

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