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C5aR1 inhibition reprograms tumor associated macrophages and reverses PARP inhibitor resistance in breast cancer

Author

Listed:
  • Xi Li

    (Oregon Health and Science University
    Huazhong University of Science and Technology)

  • Alfonso Poire

    (Oregon Health and Science University)

  • Kang Jin Jeong

    (Oregon Health and Science University)

  • Dong Zhang

    (Oregon Health and Science University)

  • Tugba Yildiran Ozmen

    (Oregon Health and Science University)

  • Gang Chen

    (Huazhong University of Science and Technology)

  • Chaoyang Sun

    (Huazhong University of Science and Technology)

  • Gordon B. Mills

    (Oregon Health and Science University)

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.

Suggested Citation

  • Xi Li & Alfonso Poire & Kang Jin Jeong & Dong Zhang & Tugba Yildiran Ozmen & Gang Chen & Chaoyang Sun & Gordon B. Mills, 2024. "C5aR1 inhibition reprograms tumor associated macrophages and reverses PARP inhibitor resistance in breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48637-y
    DOI: 10.1038/s41467-024-48637-y
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