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Bone metastases diminish extraosseous response to checkpoint blockade immunotherapy through osteopontin-producing
Jia-Nan Cheng1, Zheng Jin2, Chunxia Su3
1Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China; Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, China.
Abstract:
Bone metastatic lesions typically associate with suboptimal responses to immune checkpoint blockade (ICB) therapies. In this study, we observed that across multiple clinical cohorts and a variety of mouse models, the presence of osseous metastases induces ICB resistance in extraosseous tumors. Mechanistically, this long-distance communication is mediated by osseous tumor-conditioned osteoclasts producing osteopontin (OPN). Through circulation, OPN reprograms the extraosseous tumor microenvironment and impairs T cell recruitment and differentiation of CD8+TCF1+ precursor cells, an essential population for ICB efficacy. In mice, ICB responsiveness is restored by αRANKL blockade of osteoclastogenesis, neutralization of OPN in circulation, or tissue-specific depletion of OPN in osteoclasts. Both the mode of action and therapeutic benefit were validated in clinical cohorts with the αRANKL-ICB combinatory regimen. These findings establish bone as a specific immunoregulatory organ exploited by tumor metastasis and suggest osteoclastogenesis as a promising target to improve ICB prognosis in patients with bone metastasis.
Insights
Bone metastases cause resistance to immune checkpoint blockade (ICB) by osteoclast-produced osteopontin (OPN). Blocking osteoclast activity or OPN restores ICB efficacy, offering new therapeutic strategies for cancer patients.
Area of Science:
- Oncology
- Immunology
- Cancer Metastasis
Background:
- Immune checkpoint blockade (ICB) therapies show limited efficacy in patients with bone metastatic lesions.
- The mechanisms by which bone metastases influence systemic anti-tumor immunity remain poorly understood.
Purpose of the Study:
- To investigate the impact of bone metastases on the efficacy of immune checkpoint blockade (ICB) in extraosseous tumors.
- To elucidate the underlying mechanisms of ICB resistance induced by bone metastases.
- To identify potential therapeutic targets to overcome ICB resistance in patients with bone metastasis.
Main Methods:
- Analysis of multiple clinical cohorts and various mouse models of cancer metastasis.
- Investigation of the role of osteoclasts and osteopontin (OPN) in mediating communication between bone metastases and extraosseous tumors.
- Evaluation of therapeutic strategies including alpha-RANKL (αRANKL) blockade, OPN neutralization, and osteoclast-specific OPN depletion in preclinical models.
- Validation of therapeutic strategies in clinical cohorts receiving αRANKL and ICB combination therapy.
Main Results:
- The presence of bone metastases was found to induce resistance to ICB in tumors located elsewhere in the body.
- Osteoclasts within osseous metastases were identified as key mediators, producing osteopontin (OPN) that circulates and reprograms the tumor microenvironment.
- OPN impairs T cell recruitment and the differentiation of essential CD8+TCF1+ precursor cells, thereby reducing ICB efficacy.
- ICB responsiveness was restored in mice through αRANKL blockade, OPN neutralization, or osteoclast-specific OPN depletion.
- Combination therapy with αRANKL and ICB demonstrated therapeutic benefit in clinical studies.
Conclusions:
- Bone metastases create an immunosuppressive environment that confers resistance to ICB by modulating osteoclast activity and osteopontin production.
- Osteoclastogenesis is identified as a critical target for improving ICB outcomes in patients with bone metastasis.
- Targeting the bone microenvironment offers a promising strategy to enhance the effectiveness of cancer immunotherapy.
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