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
View: Text | PDF
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

×

Figure 7

SPP1 blockade augments antitumor immunity and overcomes PARPi resistance.

Options: View larger image (or click on image) Download as PowerPoint
SPP1 blockade augments antitumor immunity and overcomes PARPi resistance...
(A) Treatment schematic for orthotopic implantation of Trp53−/−Brca1−/− ID8 cells, followed by niraparib (i.g.; intragastric gavage) and/or SPP1 mAb (i.p.; intraperitoneal injection) administration. Right panel: Quantification of tumor bioluminescence at endpoint (n = 5 mice/group). (B) Surgically resected tumor weight of Trp53−/−Brca1−/− ID8 tumors at endpoint (n = 5 mice/group). (C) IHC quantification of intratumoral FOXP3+ and GZMB+ cells per field (×40 magnification; n = 5 mice/group). (D) Surgically resected tumor weight of Brca2−/− E0771 tumors at endpoint, with representative images (n = 6 mice/group). (E) Flow cytometry quantification of indicated T cell subsets in E0771 tumors among different groups at endpoint (n = 6 mice/group). (F) Nearest-neighbor distance analysis from indicated cells to Tregs or PD1+ Treg in Brca2−/− E0771 tumors. Vertical dashed lines represent the median distance; heatmaps compare control versus SPP1 mAb (upper) and niraparib monotherapy versus combination therapy (lower). (G) Schematic of niraparib-resistant ID8 tumor generation and surgically resected tumor weights at endpoint (n = 5 mice/group). (H) Flow cytometry quantification of indicated cells in niraparib-resistant ID8 tumors across treatment groups at endpoint (n = 5 mice/group). (I) Nearest-neighbor distance analysis in niraparib-resistant ID8 tumors (same format as panel F). (J) Bioluminescence imaging and quantification of orthotopic Trp53−/−Brca1−/− ID8 tumors in immunodeficient BALB/c-nu mice across treatment groups at endpoint (n = 5 mice/group). (K) Surgically resected tumor weight of Brca2−/− E0771 tumors from immunodeficient BALB/c-nu mice at endpoint (n = 6 mice/group). Statistical significance was determined by 2-tailed Wilcoxon rank-sum test (A−E, G, H, J, and K), *P < 0.05, **P < 0.01, ***P < 0.001, n.s. not significant; or Kolmogorov-Smirnov test (F and I), *P < 0.001.