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C5aR1 inhibition reprograms tumor associated macrophages and reverses PARP inhibitor resistance in breast cancer.
Li, Xi; Poire, Alfonso; Jeong, Kang Jin; Zhang, Dong; Ozmen, Tugba Yildiran; Chen, Gang; Sun, Chaoyang; Mills, Gordon B.
Afiliação
  • Li X; Division of Oncological Sciences Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA. xilitongji@gmail.com.
  • Poire A; Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. xilitongji@gmail.com.
  • Jeong KJ; Division of Oncological Sciences Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
  • Zhang D; Division of Oncological Sciences Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
  • Ozmen TY; Division of Oncological Sciences Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
  • Chen G; Division of Oncological Sciences Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
  • Sun C; Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • Mills GB; Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Nat Commun ; 15(1): 4485, 2024 May 27.
Article em En | MEDLINE | ID: mdl-38802355
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Resistencia a Medicamentos Antineoplásicos / Receptor da Anafilatoxina C5a / Inibidores de Poli(ADP-Ribose) Polimerases / Macrófagos Associados a Tumor Limite: Animals / Female / Humans Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Resistencia a Medicamentos Antineoplásicos / Receptor da Anafilatoxina C5a / Inibidores de Poli(ADP-Ribose) Polimerases / Macrófagos Associados a Tumor Limite: Animals / Female / Humans Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos