Wang, Meijie

Endocrine therapy remains the cornerstone of treatment for estrogen receptor alpha (ERα)-positive breast cancer, yet the relationship between individual genetic background and molecular response to ERα-targeted therapy remains incompletely understood. Using a well-characterized panel of lymphoblastoid cell lines (LCLs), we performed genome-wide pharmacogenomic expression quantitative trait locus (PGx-eQTL) analysis to identify estradiol (E2)- and tamoxifen (TAM)-induced SNP-gene pairs. PGx-eQTL signals were integrated with previously published breast cancer genome-wide association study datasets to examine their association with clinically relevant breast cancer phenotypes. We identified two ER-mediated PGx-eQTL SNP-gene pairs associated with breast cancer prognosis post-treatment with E2 or TAM. Notable loci included E2-regulated MRPL15 and TAM-regulated SYCP3, which have effects in a genotype-dependent manner, with genotype-dependent survival outcomes, from worse to better relapse-free survival. Similar endocrine-therapy effects on patient survival and breast cancer risk were observed in SIK2, post TAM-treatment, and in LSM4 with E2-treatment. Moreover, qRT-PCR validation in an independent LCL panel confirmed the genotype-specificity of these signals. Overall, we identified ER-mediated PGx-eQTL SNP-gene pairs which represent potential pharmacogenomic tools for identifying patients likely to benefit from ERα-targeted endocrine therapy, offering a foundation for more genotype-informed individualized treatment decisions in breast cancer.

Abstract Background: PD-L1 is best known for suppressing antitumor immunity at the cell surface, yet emerging evidence suggests additional nuclear functions. Previous studies from our laboratory demonstrated that nuclear PD-L1 interacts with the cohesin complex to maintain chromosomal stability. However, the upstream regulatory mechanism governing this interaction and its immunological consequences remain unknown. Methods and Results: Using acetylation-site prediction, mutagenesis, and structural modeling, we identified lysine 178 (human) / 177 (mouse) as a conserved acetylation switch regulating PD-L1 function. Deacetylation of PD-L1 (K178R/K177R) disrupted PD-L1-PDS5B/cohesin binding without affecting subcellular localization. This led to defective sister chromatid cohesion, micronuclei formation, and cytosolic DNA accumulation. RNA-seq, qPCR, and immunoblotting demonstrated robust activation of the cGAS-STING-IFN-γ signaling axis and enhanced MHC-I antigen-presentation machinery in PD-L1 K178R cells. Functionally, K178R cells proliferated more slowly and were highly susceptible to PBMC-mediated killing in co-culture assays, with further enhancement upon anti-PD-L1 antibody treatment. In xenograft models (NSG mice), tumors expressing PD-L1 K178R grew significantly slower than WT. In immunocompetent C57BL/6 syngeneic models, PD-L1 K177R tumors showed reduced growth and heightened responsiveness to PD-L1 blockade. Structural and biochemical analyses confirmed that PD-L1 acetylation at K178/K177 stabilizes its interaction with the cohesin complex, thereby preventing chromosomal instability-induced immune activation. Conclusions: We identify a conserved PD-L1 acetylation switch that couples cohesin stability to innate immune activation. PD-L1 deacetylation promotes chromosomal instability, activates cGAS-STING-IFN-γ signaling, enhances antigen presentation, and sensitizes tumors to PD-L1 immunotherapy. These findings uncover a previously unrecognized regulatory axis linking tumor genomic integrity to immune recognition, providing a mechanistic foundation for targeting PD-L1 acetylation in cancer treatment. Citation Format: Meijie Wang, Jia Yu, Liewei Wang. A pd-l1 acetylation switch coordinates chromosome cohesion and antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7391.

Abstract In many cancers, a major barrier to effective immunotherapy is the dominance of tumor-associated myeloid cells (TAMs), which establish a profoundly immunosuppressive tumor microenvironment (TME). This challenge is particularly pronounced in glioblastoma (GBM), where myeloid cells represent the predominant immune population and actively suppress antitumor immunity. Identifying targets that can reprogram TAMs from an immunosuppressive state toward a pro-inflammatory, antigen-presenting phenotype remains a critical unmet need. Here, we identify the voltage-gated proton channel Hv1 as an immune-restricted regulator of glioma-associated macrophage function. Hv1 is notable not only for its immune-specific expression but also for its established roles in central nervous system (CNS) pathologies, where Hv1 depletion alters microglial and macrophage polarization, reduces myeloid accumulation, dampens inflammatory cytokine production, and limits secondary tissue damage. However, Hv1’s role in shaping the GBM immune landscape—particularly in vivo—has remained poorly understood due to low Hvcn1 transcript abundance and the lack of reliable antibodies and genetic tools. Given the dominance of myeloid cells in GBM and their central role in tumor immune regulation, we sought to define Hv1 function within this highly immunosuppressive brain TME. Analysis of patient datasets revealed that elevated Hv1 expression correlates with poor clinical prognosis. Consistently, Hv1 loss significantly prolonged survival in multiple murine glioma models. Using in vivo two-photon imaging and spectral flow cytometry, we show that Hv1 depletion reprograms TAMs toward an anti-tumor phenotype characterized by enhanced tumor cell phagocytosis, improved antigen presentation, and increased T cell infiltration. By generating new Hv1 reporter and conditional mouse lines, we further demonstrate that tumor-associated microglia and infiltrating macrophages are the principal sources of Hv1 and markedly upregulate its expression in response to glioma. Notably, selective deletion of Hv1 in infiltrating macrophages phenocopied the survival benefit observed with global Hv1 loss. Mechanistically, using mass spectrometry and genetic models, we identify the Stimulator of Interferon Genes (STING) as a previously unrecognized binding partner of Hv1, placing Hv1 within the STING signaling pathway, a central regulator of innate and adaptive immune responses. Together, these findings fill a critical gap in understanding myeloid Hv1 function in GBM and identify Hv1 as a promising target for reprogramming the tumor immune microenvironment. Citation Format: Jiaying Zheng, Lingxiao Wang, Shunyi Zhao, Katayoun Ayasoufi, Meijie Wang, Praveen N. Pallegar, Peter R. Strege, Langni Liu, Yushan Wan, Wenjing Zhang, Emma N. Goddery, Manling Xie, Arthur Beyder, Aaron J. Johnson, Long-Jun Wu. Myeloid Hv1-STING axis tunes glioma immunity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A016.