American Association for Cancer Research
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mct-23-0303_supplementary_fig.s4_suppsf4.pdf (1.47 MB)

Supplementary Fig. S4 from Combination Therapies to Improve the Efficacy of Immunotherapy in Triple-negative Breast Cancer

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posted on 2023-11-01, 08:03 authored by Maša Alečković, Zheqi Li, Ningxuan Zhou, Xintao Qiu, Bethlehem Lulseged, Pierre Foidart, Xiao-Yun Huang, Kodie Garza, Shaokun Shu, Nikolas Kesten, Rong Li, Klothilda Lim, Ana C. Garrido-Castro, Jennifer L. Guerriero, Jun Qi, Henry W. Long, Kornelia Polyak

Supplementary Fig. S4 shows additional RNA-seq data analyses.

Funding

National Cancer Institute (NCI)

United States Department of Health and Human Services

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Susan G. Komen (SGK)

Ludwig Center at Harvard (Ludwig Center)

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ARTICLE ABSTRACT

Immune checkpoint inhibition combined with chemotherapy is currently approved as first-line treatment for patients with advanced PD-L1–positive triple-negative breast cancer (TNBC). However, a significant proportion of metastatic TNBC is PD-L1–negative and, in this population, chemotherapy alone largely remains the standard-of-care and novel therapeutic strategies are needed to improve clinical outcomes. Here, we describe a triple combination of anti-PD-L1 immune checkpoint blockade, epigenetic modulation thorough bromodomain and extra-terminal (BET) bromodomain inhibition (BBDI), and chemotherapy with paclitaxel that effectively inhibits both primary and metastatic tumor growth in two different syngeneic murine models of TNBC. Detailed cellular and molecular profiling of tumors from single and combination treatment arms revealed increased T- and B-cell infiltration and macrophage reprogramming from MHCIIlow to a MHCIIhigh phenotype in mice treated with triple combination. Triple combination also had a major impact on gene expression and chromatin profiles shifting cells to a more immunogenic and senescent state. Our results provide strong preclinical evidence to justify clinical testing of BBDI, paclitaxel, and immune checkpoint blockade combination.

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    Molecular Cancer Therapeutics

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    Keywords

    Breast CancerEpigeneticsEpigenomicsHistone ModificationImmunotherapyCombination immunotherapy

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