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Isolation Protocol of Mouse Monocyte-derived Dendritic Cells and Their Subsequent In Vitro Activation with Tumor Immune Complexes
Published on: May 31, 2018
Cancer immunotherapy targeting murine myeloid cells requires endosomal pattern recognition
Yueyun Pan1, Shengduo Pei1, Heng Liang1
1Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna Campus, Stockholm, Sweden.
Abstract:
Immunotherapy is now an established and efficient treatment option for many cancer patients. However, a proportion of patients still experience poor outcomes due to treatment resistance. Thus, a clear understanding of key mechanisms of resistance is needed for the development of new treatments. Here, we employ mouse models to explore an immunotherapeutic approach based on anti-MARCO (αMARCO) and anti-PD-L1 (αPD-L1) antibody-mediated targeting of tumor-associated macrophages (TAM). We demonstrate that effective immunotherapy relies on a functional endosomal pattern recognition machinery. We determine that endosomal Toll-like receptors (TLR), specifically TLR9, precondition macrophages to respond to αMARCO treatment by regulating the transcription of inflammasome components. Absence of TLRs renders TAMs unresponsive to treatment while retaining an immunosuppressive phenotype. Thus, we uncover the intracellular TLR signalling as a feature of immunotherapy efficacy, required to sensitise TAMs to treatment, and indicate that TLR targeting could be exploited to improve immunotherapeutic outcomes.
Insights
Intracellular Toll-like receptor (TLR) signaling is crucial for effective cancer immunotherapy. Targeting TLRs can sensitize tumor-associated macrophages (TAMs) to treatments like anti-MARCO and anti-PD-L1 antibodies, improving patient outcomes.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Immunotherapy is a key cancer treatment, but resistance limits efficacy.
- Understanding resistance mechanisms is vital for developing improved therapies.
- Tumor-associated macrophages (TAMs) are critical players in the tumor microenvironment and immunotherapy response.
Purpose of the Study:
- To investigate the role of intracellular pattern recognition machinery in immunotherapy resistance.
- To explore the potential of targeting TAMs using anti-MARCO and anti-PD-L1 antibodies.
- To identify mechanisms that sensitize TAMs to immunotherapeutic agents.
Main Methods:
- Utilized mouse models to study immunotherapy targeting TAMs.
- Investigated the function of endosomal Toll-like receptors (TLRs), specifically TLR9.
- Assessed the impact of TLR signaling on macrophage response to anti-MARCO treatment.
Main Results:
- Effective immunotherapy requires functional endosomal pattern recognition machinery.
- Endosomal TLR9 signaling preconditions macrophages for anti-MARCO treatment by regulating inflammasome components.
- Absence of TLRs results in unresponsive, immunosuppressive TAMs, hindering treatment efficacy.
Conclusions:
- Intracellular TLR signaling is essential for sensitizing TAMs to immunotherapy.
- Targeting TLRs presents a potential strategy to enhance immunotherapeutic outcomes in cancer patients.
- This study highlights the importance of the endosomal TLR pathway in overcoming immunotherapy resistance.
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