Tumor Microenvironment Modulates Immunological Outcomes of Myeloid Cells with mTORC1 Disruption

Area of Science:

• Oncology
• Immunology
• Cell Biology

Background:

• The mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway's role in myeloid cells during tumor development is not fully understood.
• Myeloid cells, particularly macrophages, play critical roles in shaping the tumor microenvironment and influencing anti-tumor immunity.

Purpose of the Study:

• To investigate the function of mTORC1 in myeloid cells within the context of Lewis lung carcinoma (LLC) tumor growth and metastasis.
• To determine how disrupting mTORC1 signaling in myeloid cells affects tumor-associated macrophages (TAMs) and overall anti-tumor immune responses.

Main Methods:

• Utilized myeloid cell-specific Raptor knockout (KO) mice to conditionally deplete mTORC1 in myeloid cells.
• Analyzed tumor growth, macrophage function (including immunosuppressive activity and M1-like differentiation), cytokine production (TNF-α), and lung metastasis in both subcutaneous and lung metastasis models.

Main Results:

• In subcutaneous LLC tumors, mTORC1 depletion in myeloid cells reduced TAM immunosuppressive function and TNF-α production but impaired M1-like TAM differentiation due to decreased CD115 expression.
• Conversely, disruption of mTORC1 in myeloid cells promoted lung cancer metastasis, characterized by an accumulation of immunosuppressive interstitial/metastasis-associated macrophages and reduced Th1 responses.

Conclusions:

• The tumor microenvironment differentially dictates the immunological outcomes of myeloid cells upon mTORC1 disruption.
• mTORC1 signaling in myeloid cells has context-dependent roles, impacting tumor growth and metastasis differently based on the tumor microenvironment and cancer type.