Abstract P1-04-11: Pd-l1-expressing b-cells promote murine breast cancer development and mediate the response to anti-pd-l1 immune checkpoint inhibitor
Authors: Mustafa Tamim Alam Khan, Christian Cervantes, Suryavathi Viswanadhapalli, Yan Hui, Ratna Vadlamudi, Zhenming Xu
Journal: Cancer Research (2022)

Abstract B cells promote tumor development in murine models of breast cancer (BCa), including - as we have shown - by producing pleiotropic cytokine IL-27, which upregulates expression of the PD-L1 immune checkpoint in BCa cells and tumor-infiltrating B cells (TIL-Bs). Paradoxically, B cell activation has been shown to predict the positive response to immune checkpoint inhibitors (ICIs) by murine BCa tumors and melanoma, sarcoma and kidney cancer in patients. Here, we have addressed the role of B cell-expressed PD-L1 in BCa development and responses to ICIs by generating conditional knockout (KO) mice in which Cd274 (encoding PD-L1) was ablated only in activated B cells (AicdacreCd274fl/fl). Tumor development in AicdacreCd274fl/fl mice from engrafted syngeneic ER+ E0071 BCa cells was significantly delayed, albeit not abolished (as occurring in mice lacking B cells), in association with increased B-cell expression of CD86, a key agonistic ligand for T cell-expressed CD28, a co-stimulatory receptor whose function is inhibited by the PD-L1/PD-1 immune checkpoint in exhausted tumor-infiltrating CD8+ T cells. The heightened B-cell CD86 expression in AicdacreCd274fl/fl mice was recapitulated in AicdacreCd274fl/fl B cells stimulated in vitro by CD154, a T helper cell stimulus critical for B cell activation and differentiation as well as the antibody response. Accordingly, AicdacreCd274fl/fl mice displayed an increased antibody response to a T-dependent antigen. Likewise, treatment with the anti-PD-L1 (αPD-L1) ICI boosted wildtype B cells stimulated with CD154 in vitro to express CD86 and differentiate into potentiated plasma cells. It also effectively regressed the growth of pre-developed E0071 tumor in C57 and AicdacreCd274+/fl mice by rejuvenating tumor-infiltrating CD8+ T cells, likely through activation of previously dampened CD28 signaling. By contrast, residual tumors that had eventually developed in AicdacreCd274fl/fl mice failed to respond to αPD-L1 and continued to grow at a pace comparable to tumors treated with an isotype-matched control antibody, showing that the full anti-tumor efficacy of αPD-L1 was mediated mainly by PD-L1-expressing B cells, but not other immune cell types. Thus, PD-L1+ TIL-Bs use PD-L1 to impose a “brake” on the host anti-tumor activity, but are directly targeted by αPD-L1 to relieve the brake, “jump-start” the CD86:CD28 signaling and potentiate the anti-tumor response, thereby providing a mechanistic explanation for the opposing roles of B cells in murine BCa development and ICI responses. Our findings also provide a strong rationale to investigate the activation of PD-L1-expressing TIL-Bs by Atezolizumab® (αPD-L1) in BCa patients to underpin the patient response to this ICI. Citation Format: Mustafa Tamim Alam Khan, Christian Cervantes, Suryavathi Viswanadhapalli, Yan Hui, Ratna Vadlamudi, Zhenming Xu. Pd-l1-expressing b-cells promote murine breast cancer development and mediate the response to anti-pd-l1 immune checkpoint inhibitor [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-04-11.