Importance of Cellular Microenvironment and Circulatory Dynamics in B Cell Immunotherapy

TLDR

B cell immunotherapy is a mainstay for lymphomas and autoimmune diseases, yet the contribution of the microenvironment to its efficacy remains unknown. The study investigates which in vivo factors regulate B cell immunotherapy mechanisms by treating hCD20‑expressing mice with anti‑hCD20 monoclonal antibodies. Using a murine model that expresses human CD20, the authors mimic human B cell depletion by administering anti‑hCD20 mAbs to assess how microenvironmental signals influence therapy. Microenvironmental signals—including BLyS, integrin‑mediated homeostasis, and B cell circulatory dynamics—create distinct mechanisms and sensitivities to anti‑hCD20 therapy, revealing new insights and therapeutic opportunities for cancers and autoimmune diseases.

Abstract

Abstract B cell immunotherapy has emerged as a mainstay in the treatment of lymphomas and autoimmune diseases. Although the microenvironment has recently been demonstrated to play critical roles in B cell homeostasis, its contribution to immunotherapy is unknown. To analyze the in vivo factors that regulate mechanisms involved in B cell immunotherapy, we used a murine model for human CD20 (hCD20) expression in which treatment of hCD20+ mice with anti-hCD20 mAbs mimics B cell depletion observed in humans. We demonstrate in this study that factors derived from the microenvironment, including signals from the B cell-activating factor belonging to the TNF family/BLyS survival factor, integrin-regulated homeostasis, and circulatory dynamics of B cells define distinct in vivo mechanism(s) and sensitivities of cells in anti-hCD20 mAb-directed therapies. These findings provide new insights into the mechanisms of immunotherapy and define new opportunities in the treatment of cancers and autoimmune diseases.