Academic Journal
C5aR1 inhibition reprograms tumor associated macrophages and reverses PARP inhibitor resistance in breast cancer
| العنوان: | C5aR1 inhibition reprograms tumor associated macrophages and reverses PARP inhibitor resistance in breast cancer |
|---|---|
| المؤلفون: | Xi Li, Alfonso Poire, Kang Jin Jeong, Dong Zhang, Tugba Yildiran Ozmen, Gang Chen, Chaoyang Sun, Gordon B. Mills |
| المصدر: | Nature Communications, Vol 15, Iss 1, Pp 1-20 (2024) |
| بيانات النشر: | Nature Portfolio, 2024. |
| سنة النشر: | 2024 |
| المجموعة: | LCC:Science |
| مصطلحات موضوعية: | Science |
| الوصف: | Abstract Although Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have been approved in multiple diseases, including BRCA1/2 mutant breast cancer, responses are usually transient requiring the deployment of combination therapies for optimal efficacy. Here we thus explore mechanisms underlying sensitivity and resistance to PARPi using two intrinsically PARPi sensitive (T22) and resistant (T127) syngeneic murine breast cancer models in female mice. We demonstrate that tumor associated macrophages (TAM) potentially contribute to the differential sensitivity to PARPi. By single-cell RNA-sequencing, we identify a TAM_C3 cluster, expressing genes implicated in anti-inflammatory activity, that is enriched in PARPi resistant T127 tumors and markedly decreased by PARPi in T22 tumors. Rps19/C5aR1 signaling is selectively elevated in TAM_C3. C5aR1 inhibition or transferring C5aR1hi cells increases and decreases PARPi sensitivity, respectively. High C5aR1 levels in human breast cancers are associated with poor responses to immune checkpoint blockade. Thus, targeting C5aR1 may selectively deplete pro-tumoral macrophages and engender sensitivity to PARPi and potentially other therapies. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2041-1723 |
| Relation: | https://doaj.org/toc/2041-1723 |
| DOI: | 10.1038/s41467-024-48637-y |
| URL الوصول: | https://doaj.org/article/87332cc7bc164961bc45782eb7c90b2e |
| رقم الانضمام: | edsdoj.87332cc7bc164961bc45782eb7c90b2e |
| قاعدة البيانات: | Directory of Open Access Journals |
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