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Tumor-associated macrophages regulate the function of cytotoxic T lymphocyte through PD-1/PD-L1 pathway in multiple

Jiangbo Zhang1,2, Zhaoyun Liu1, Panpan Cao1

  • 1Department of Hematology, Tianjin Medical University General Hospital, Tianjin, People's Republic of China.

Cancer Medicine
|May 20, 2022
PubMed
Abstract

Insights

Tumor-associated macrophages (TAMs) increase in multiple myeloma (MM), suppressing cytotoxic T lymphocytes (CTLs) via PD-1/PD-L1 signaling. Inhibiting CSF1R or PD-L1 partially restores CTL function, suggesting therapeutic targets for MM immune escape.

Area of Science:

  • Immunology
  • Oncology
  • Cancer Biology

Background:

  • Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment, originating from peripheral blood monocytes.
  • TAMs play a role in the immune evasion of cancer cells, including plasma cells in multiple myeloma (MM).
  • Understanding TAM function in MM is crucial for developing novel immunotherapies.

Purpose of the Study:

  • To investigate the role of TAMs in the bone marrow of multiple myeloma patients.
  • To analyze the expression of TAMs, CSF1/CSF1R, and PD-1/PD-L1 in newly diagnosed MM (NDMM) and remission patients.
  • To evaluate the impact of TAMs on cytotoxic T lymphocyte (CTL) function and the potential of targeting TAMs.

Main Methods:

  • Flow cytometry was used to quantify TAMs, CSF1 on CD138+ cells, CSF1R on macrophages, PD-1 on CD8+ T cells, and PD-L1 on TAMs in 86 MM patients and 28 healthy controls.
  • Bone marrow mononuclear cells (BMMNCs) and CD8+ T cells were isolated and cultured.
  • A co-culture system of TAMs and CD8+ T cells was established, with and without CSF1R inhibitor and anti-PD-L1 antibody, to assess perforin and granzyme B levels.

Main Results:

  • TAMs, CSF1 on plasma cells, CSF1R on macrophages, PD-1 on T cells, and PD-L1 on TAMs were significantly elevated in NDMM patients compared to remission patients and healthy controls.
  • TAM levels decreased upon CSF1R inhibitor treatment.
  • Co-culture of T cells with TAMs reduced cytotoxic markers (perforin, granzyme B), an effect partially reversed by CSF1R inhibitor and anti-PD-L1 antibody treatment.

Conclusions:

  • Elevated TAMs in MM patients contribute to immune suppression by inhibiting CTL function through the PD-1/PD-L1 pathway.
  • Targeting the CSF1R/CSF1 axis and the PD-1/PD-L1 pathway holds promise for overcoming immune escape in multiple myeloma.
  • These findings highlight TAMs as a potential therapeutic target for enhancing anti-myeloma immunity.
Keywords:
CD8 + T cellsCSF1RPD-1/PD-L1TAMsmultiple myeloma

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