Tumor cell–derived IFN spatially reprograms osteopontin-enriched macrophage niches to promote PARP inhibitor resistance
Dan Liu, Kangjia Tao, Cheng Xu, Wen Yang, Chujun Cai, Cui Feng, Kairong Xiong, Sisi Wu, Yaying Lin, Zikun Peng, Jianhua Chi, Wen Pan, Qing Zhong, Jiahao Liu, Xiong Li, Xingzhe Liu, Dongchen Zhou, Ding Ma, Guang-Nian Zhao, Yu Xia, Yong Fang, Qinglei Gao
Dan Liu, Kangjia Tao, Cheng Xu, Wen Yang, Chujun Cai, Cui Feng, Kairong Xiong, Sisi Wu, Yaying Lin, Zikun Peng, Jianhua Chi, Wen Pan, Qing Zhong, Jiahao Liu, Xiong Li, Xingzhe Liu, Dongchen Zhou, Ding Ma, Guang-Nian Zhao, Yu Xia, Yong Fang, Qinglei Gao
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Research Article Immunology Oncology

Tumor cell–derived IFN spatially reprograms osteopontin-enriched macrophage niches to promote PARP inhibitor resistance

Abstract

Poly (ADP-ribose) polymerase inhibitors (PARPis) benefit homologous recombination-deficient (HRD) malignancies, yet resistance remains a major challenge. Leveraging specimens from a prospective neoadjuvant niraparib monotherapy trial in treatment-naive, high-grade serous ovarian cancer, we integrated PhenoCycler-Fusion spatial profiling, scRNA-Seq, and multiplex immunohistochemistry to identify 2 therapeutic-modulated cellular neighborhoods: an IFN+ tumor cell–enriched niche that expands in resistant lesions and a niche enriched in tumor-associated macrophage (TAM) that persists but acquires enhanced immunosuppressive features. Mechanistically, sustained tumor cell–derived IFN induced osteopontin (SPP1) expression in TAMs via STAT signaling, creating immunosuppressive niches enriched in Tregs and myofibroblastic cancer–associated fibroblasts with intensified cell-cell interactions. SPP1 directly suppressed T cell signaling and effector function. High baseline SPP1+ cells predicted lower response rate (30.0% vs. 76.2%; P = 0.021) and shorter progression-free survival (median 13.5 vs. 28.3 months; P = 0.0006). In HRD mouse models, SPP1 blockade restored PARPi sensitivity, reversed acquired resistance, and enhanced T cell cytotoxicity—effects abrogated in immunodeficient mice, confirming immune dependence. These data establish a spatial IFN-SPP1 axis whereby persistent tumor cell IFN reprograms TAMs to promote PARPi resistance, position SPP1 as a key therapeutic target and prognostic biomarker for this therapy, and underscore therapeutic potential of microenvironment-targeted strategies to overcome PARPi resistance.

Authors

Dan Liu, Kangjia Tao, Cheng Xu, Wen Yang, Chujun Cai, Cui Feng, Kairong Xiong, Sisi Wu, Yaying Lin, Zikun Peng, Jianhua Chi, Wen Pan, Qing Zhong, Jiahao Liu, Xiong Li, Xingzhe Liu, Dongchen Zhou, Ding Ma, Guang-Nian Zhao, Yu Xia, Yong Fang, Qinglei Gao

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Figure 6

SPP1-mediated immunosuppression correlates with poor prognosis after PARPi therapy.

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SPP1-mediated immunosuppression correlates with poor prognosis after PAR...
(A) Spearman correlation analysis between global SPP1 expression and proportion of M2-TAMs in macrophages, myCAFs in fibroblasts, and Tregs in CD4+ T cells in HGSOC using the GSE180661 scRNA-Seq dataset (n = 136). (B) Spearman correlation analysis (as in panel A) in breast cancer using the GSE176078 scRNA-Seq data set (n = 26). (C) Western blot analysis of the TCR signaling pathway activation in T cells stimulated with or without TCR, recombinant SPP1 (rSPP1), or anti-CD44 antibody. (D) Flow cytometry quantification of IFN-γ and TNF-α expression in CD4+ cells (upper) and CD8+ T cells (lower) after stimulation with or without rSPP1 or macrophage-conditioned medium (MCM), with or without anti-CD44 antibody (n = 4). Statistical significance was determined by Wilcoxon test with Benjamini-Hochberg correction. (E) Flow cytometry quantification of IFN-γ and TNF-α expression in CD4+ (upper) and CD8+ T cells (lower) treated with or without tumor-conditioned medium (TCM) and SPP1 mAb (n = 4). Statistical significance was determined by Wilcoxon test with Benjamini-Hochberg correction. (F) Representative images of residual ovarian tumor cells following co-culture with OT1 mouse-derived T cells (left). Lactate dehydrogenase (LDH) cytotoxicity assay results for different tumor cell lines (n = 8, right). (G) Clinical response rate (complete response, [CR] plus partial response [PR]) to niraparib monotherapy in the NANT cohort, stratified by low (n = 21) versus high (n = 10) density of SPP1+ cell infiltration. Statistical significance was determined by 2-sided Fisher’s exact test. (H) Kaplan-Meier estimates of progression-free survival (PFS) in the NANT trial, stratified by low (n = 28) and high (n = 11) density of SPP1+ cell infiltration. One patient was excluded from PFS analysis owing to loss of follow-up. Statistical significance was determined by log-rank test. *P < 0.05, **P < 0.01, ***P < 0.001. HR, hazard ratio.