Osteopontin mediates acquired resistance to hypoxia-inducing antiangiogenics and promotes anti–PD-L1 refractoriness in breast cancer models
Jose Luis Ruiz-Sepulveda, Maria J. Bueno, Silvana Mouron, Veronica Jimenez-Renard, Manuel Muñoz, Manuel Moradiellos, Leonardo D. Garma, Luis García-Jimeno, Adam W. Watson, Ghassan Mouneimne, Solip Park, Rebeca Jimeno, Miguel Quintela-Fandino
Jose Luis Ruiz-Sepulveda, Maria J. Bueno, Silvana Mouron, Veronica Jimenez-Renard, Manuel Muñoz, Manuel Moradiellos, Leonardo D. Garma, Luis García-Jimeno, Adam W. Watson, Ghassan Mouneimne, Solip Park, Rebeca Jimeno, Miguel Quintela-Fandino
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Research Article Immunology Oncology

Osteopontin mediates acquired resistance to hypoxia-inducing antiangiogenics and promotes anti–PD-L1 refractoriness in breast cancer models

Abstract

Resistance to antiangiogenics is a major challenge in cancer therapy. These agents can either normalize or exacerbate tumor vascular abnormality and hypoxia. The mechanisms of resistance remain unclear in the latter setting. By integrating data from mouse models and clinical trials, we showed that hypoxia-inducing anti-VEGF therapy upregulated programmed cell death ligand 1 (PD-L1), yet failed to sensitize tumors to PD-L1 blockade. Mechanistically, early hypoxic stress triggered epithelial osteopontin (SPP1) production, which recruited monocytes and skewed macrophages toward M2 states, suppressing T cell cytotoxicity. Pharmacological SPP1 depletion impeded the development of hypoxia, reduced M2 infiltration, restored T cell activity, and enabled synergy between antiangiogenics and anti–PD-L1. Genetic dissection — tumor-epithelial Spp1-KO grafts and bone marrow chimeras generated by lethal irradiation and reconstitution with Spp1–/– or WT hematopoietic donors — showed that myeloid SPP1 contributed only marginally compared with epithelial SPP1. These findings identified SPP1 as a central mediator of resistance to hypoxia-inducing antiangiogenics, contributed to a comprehensive model of antiangiogenic resistance, and supported SPP1-targeted strategies to personalize immunotherapy and antiangiogenic therapy according to tumor hypoxia.

Authors

Jose Luis Ruiz-Sepulveda, Maria J. Bueno, Silvana Mouron, Veronica Jimenez-Renard, Manuel Muñoz, Manuel Moradiellos, Leonardo D. Garma, Luis García-Jimeno, Adam W. Watson, Ghassan Mouneimne, Solip Park, Rebeca Jimeno, Miguel Quintela-Fandino

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Figure 7

Systemic osteopontin blockade restores immune control, and tumor cells are the predominant source of SPP1.

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Systemic osteopontin blockade restores immune control, and tumor cells a...
(A) Myeloid cells, macrophages, and myeloid-derived suppressor cells in tumors from the indicated treatment groups (VT: n = 11; anti-SPP1: n = 4; B20 LH: n = 9; B20 HH: n = 10). One-way ANOVA with Tukey’s post hoc test for multiple comparisons. (B) M1 and M2 macrophage fractions across the same treatment groups. (VT: n = 11; anti-SPP1: n = 4; B20 LH: n = 9; B20 HH: n = 10). One-way ANOVA with Tukey’s post hoc test for multiple comparisons. (C) Tumor growth and OS after anti–PD-L1, anti-SPP1, B20-4.1.1, or their combinations. Controls (n = 36); anti–PD-L1 (n = 23); anti-SPP1 (n = 5); anti-SPP1 + anti–PD-L1 (n = 6); HH (n = 20); LH (n = 10); B20-4.1.1+anti-SPP1 (n = 8); B20-4.1.1 + anti-SPP1 + anti–PD-L1 (n = 7). Two-way ANOVA followed by Tukey’s multiple-comparison test. (D) Phenotypic consequences of tumor cell versus myeloid SPP1 depletion, showing a predominant contribution of the tumor-epithelial compartment (n = 7–21 mice per group). Two-way ANOVA followed by Tukey’s multiple-comparison test. (E) Hypoxia development (in VT- or B20-4.1.1–treated tumors) is partially corrected in the epithelial KO model (n = 5–7) but not in the BM model (n = 9–19). One-way ANOVA with Tukey’s post hoc test for multiple comparisons. Data are presented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.