Tumor-associated CD19+CD39- B regulatory cells deregulate class-switch recombination to suppress antibody responses.
Subhadip PatiSumon MukherjeeSaikat DuttaAharna GuinDia RoySayantan BoseSilpita PaulSudipto SahaSankar BhattacharyyaPratyush DattaJayati ChakrabortyDiptendra K SarkarGaurisankar SaPublished in: Cancer immunology research (2022)
B cells are an essential component of humoral immunity. Their primary function is to mount antigen-specific antibody responses to eliminate pathogens. Despite an increase in B-cell number, we found that serum-IgG levels were low in breast cancer patients. To solve this conundrum, we used high-dimensional flow-cytometry to analyse the heterogeneity of B-cell populations and identified a tumor-specific CD19+CD24hiCD38hi IL10-producing B regulatory (Breg) cell subset. Although IL10 is a Breg-cell marker, being an intracellular protein, it is of limited value for Breg-cell isolation. Highly-expressed Breg cell-surface proteins CD24 and CD38 also impede the isolation of viable Breg cells. These are hurdles that limit understanding of Breg-cell functions. Our transcriptomic analysis identified, CD39-negativity as an exclusive, sorting-friendly surface marker for tumor-associated Breg cells. We found that the identified CD19+CD39-IL10+ B-cell population was suppressive in nature as it limited T helper-cell proliferation, type-1 cytokine production, and T effector-cell survival, and augmented CD4+FOXP3+ Treg-cell generation. These tumor-associated Breg cells were also found to restrict autologous T follicular helper (Tfh)-cell expansion and IL21 secretion, thereby inhibiting germinal transcript formation and activation-induced cytidine deaminase (AID) expression involved in H-chain class-switch recombination. This isotype-switching abnormality was shown to hinder B-cell differentiation into class-switched memory B cells and subsequent high-affinity antibody-producing plasma B cells, which collectively led to the dampening of IgG-mediated antibody responses in cancer patients. As low IgG is associated with poor prognosis in cancer patients, Breg-cell depletion could be a promising future therapy for boosting plasma B cell-mediated antibody responses.
Keyphrases
- single cell
- poor prognosis
- cell therapy
- induced apoptosis
- cell proliferation
- regulatory t cells
- long non coding rna
- rna seq
- cell cycle arrest
- dna damage
- flow cytometry
- immune response
- transcription factor
- cell death
- endoplasmic reticulum stress
- oxidative stress
- small molecule
- multidrug resistant
- dna repair
- cell cycle
- antimicrobial resistance
- binding protein
- diabetic rats