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Antibody-dependent cellular phagocytosis (ADCP) by macrophages unexpectedly suppresses anti-tumor immunity. Targeting PD-L1 and IDO alongside therapeutic antibodies enhances anti-cancer effects.

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Area of Science:

  • Immunology
  • Oncology
  • Cancer Therapy

Background:

  • Antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) are key mechanisms for therapeutic antibodies against cancer.
  • The precise role of ADCP in modulating the tumor microenvironment remains incompletely understood.

Purpose of the Study:

  • To investigate the impact of ADCP on immune cell-mediated anti-tumor responses.
  • To elucidate the molecular mechanisms by which ADCP influences the tumor microenvironment.
  • To explore combination therapies for enhanced anti-cancer efficacy.

Main Methods:

  • Investigated ADCP in breast cancer and lymphoma models.
  • Utilized FcγR signaling, AIM2 inflammasome activation, and phagosomal integrity assays.
  • Assessed upregulation of PD-L1 and IDO in macrophages.
  • Evaluated combined treatment with anti-HER2 antibody and PD-L1/IDO inhibitors in mouse models.
  • Analyzed tumor-associated macrophages (TAMs) in HER2+ breast cancer patients receiving neoadjuvant trastuzumab.

Main Results:

  • Macrophages mediating ADCP were found to inhibit NK cell-mediated ADCC and T cell cytotoxicity.
  • AIM2 inflammasome activation, triggered by phagocytosed tumor DNA, upregulates PD-L1 and IDO, leading to immunosuppression.
  • Combined treatment with anti-HER2 antibody and PD-L1/IDO inhibitors improved anti-tumor immunity and therapeutic efficacy in mice.
  • Trastuzumab therapy in patients correlated with increased PD-L1 and IDO in TAMs and poorer treatment response.

Conclusions:

  • ADCP-mediating macrophages play a detrimental role in cancer immunosuppression.
  • Targeting PD-L1 and IDO in combination with therapeutic antibodies offers a promising strategy for synergistic anti-tumor effects.
  • These findings highlight the potential of combining antibody therapy with immune checkpoint blockade for improved cancer treatment outcomes.