PD-L1-expressing B cells promote murine breast cancer development and mediate response to anti-PD-L1 immune checkpoint inhibitor

Autor: Christian Cervantes, Mustafa Tamim Alam Khan, Zexuan Liu, Suryavathi Viswanadhapalli, Harshita Gupta, Tyler Curiel, Hui Yan, Ratna Vadlamudi, Zhenming Xu
Rok vydání: 2021
Předmět:
Zdroj: The Journal of Immunology. 206:56.13-56.13
ISSN: 1550-6606
0022-1767
DOI: 10.4049/jimmunol.206.supp.56.13
Popis: B cells promote tumor development in murine models of breast cancer (BCa), – as we have shown – by producing pleiotropic cytokine IL-27, which upregulates expression of PD-L1 immune checkpoint in BCa cells and tumor-infiltrating B cells (TIL-Bs). Paradoxically, B cell activation has been shown to predict a positive response to immune checkpoint inhibitors (ICIs) in murine BCa tumors and melanoma, sarcoma and kidney cancer in humans. Here, we have addressed the role of B cell-expressed PD-L1 in BCa development and responses to ICIs by generating conditional knockout 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), with a marked increase in CD86 B-cell expression, 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). The heightened B-cell CD86 expression in AicdacreCd274fl/fl mice was recapitulated in vitro using CD154, a T helper cell stimulus critical for B cell activation and differentiation. Treatment with anti-PD-L1 (aPD-L1) boosted wildtype B cells, stimulated with CD154 in vitro, to express CD86 and differentiate into potentiated plasma cells. Thus, PD-L1+ TIL-Bs use PD-L1 to impose a “brake” on host anti-tumor activity but are directly targeted by aPD-L1 to relieve the brake, which “jump-starts” CD86:CD28 signaling and potentiates the anti-tumor response. Thus, providing a mechanistic explanation for the opposing roles of B cells in murine BCa development and ICI responses.
Databáze: OpenAIRE
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