Anti-CD20 Antibody Promotes Cancer Escape via Enrichment of Tumor-Evoked Regulatory B Cells Expressing Low Levels of CD20 and CD137L

Abstract

The possible therapeutic benefits of B-cell depletion in combating tumoral immune escape have been debated. In support of this concept, metastasis of highly aggressive 4T1 breast cancer cells in mice can be abrogated by inactivation of tumor-evoked regulatory B cells (tBregs). Here we report the unexpected finding that B-cell depletion by CD20 antibody will greatly enhance cancer progression and metastasis. Both murine and human tBregs express low levels of CD20 and, as such, anti-CD20 mostly enriches for these cells. In the 4T1 model of murine breast cancer, this effect of enriching for tBregs suggests that B-cell depletion by anti-CD20 may not be beneficial at all in some cancers. In contrast, we show that in vivo targeted stimulation of B cells with CXCL13-coupled CpG-ODN can block cancer metastasis by inhibiting CD20Low tBregs. Mechanistic investigations suggested that CpG-ODN upregulates low surface levels of 4-1BBL on tBregs to elicit granzyme B-expressing cytolytic CD8+ T cells, offering some explanative power for the effect. These findings underscore the immunotherapeutic importance of tBreg inactivation as strategy to enhance cancer therapy by targeting both the regulatory and activating arms of the immune system in vivo.

Accumulation of 4-1BBL+ B cells in the elderly induces the generation of granzyme-B+ CD8+ T cells with potential antitumor activity

“…Aging mammals accumulate 4-1BBL 1 B cells and GrB 1 CD8 1 T cells Given its importance in CD8 1 T-cell induction, [22][23][24] and that B cells can elicit antitumor GrB 1 CD8 1 T cells using 4-1BBL, 21 we hypothesized that 4-1BBL 1 B cells could also be responsible for the age-associated expansion of CD8 1 CD28 Low T cells expressing GrB. 10 To test this idea, the 2 cell types were evaluated in the PB of old (79 6 6 years) and young (42 6 9 years) healthy humans.…”

“…20 We recently found that antitumor effector GrB 1 CD8 1 T cells can also be induced when tumorsupporting regulatory B cells (Bregs) are rendered into activators expressing 4-1BBL. 21 Here, given the importance of 4-1BBL in CD8 1 T-cell induction [22][23][24] and the pathogenic role of B cells in autoimmune disorders, 25,26 we hypothesized that the accumulation of 4-1BBL 1 B cells could be responsible for the expansion of GrB 1 CD8 1 T cells in the elderly. To test this idea, we evaluated 4-1BBL 1 B cells and GrB 1 CD8 1 T cells in mammals, such as in healthy human participants of the Baltimore Longitudinal Study of Aging (BLSA), rhesus macaques, and mice.…”

Identification of Potential Therapeutic Targets Among CXC Chemokines in Breast Tumor Microenvironment Using Integrative Bioinformatics Analysis

“…CXCL13, known as B lymphocyte chemoattractant (BCL), was frequently found in the interaction between cancer cells and B cells [55]. RORγt+ group 3 innate lymphoid also stimulated the expression of CXCL13 by stromal cells in the microenvironment and largely contributed to lymph node metastases [56].…”

CD20+ B-cell depletion therapy suppresses murine CD8+ T-cell–mediated immune thrombocytopenia

“…This may be related to how CD20 low 4-1BBL 1 B-regulatory cells regulate Granzyme B expression in CD8 1 T cells. 22,23 Although Granzyme B expression in CD8 1 T cells was found to be increased in follicular lymphoma patients at diagnosis, which was associated with better prognosis, it appeared unchanged in patients with ITP. 21,24 Taken together, our results suggest that in vivo Bdep therapy interferes with in vitro IL-2-dependent CD8…”