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NLRC3 enhances antitumor immunity by specifically negatively regulating M-MDSCs in a STING-dependent manner
Yuling Fu1, Xiaoxia Zhan2, Shousheng Liu3
1Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, The Second Affiliated Hospital, The State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China.
Abstract:
NOD-like receptor (NLR) family CARD domain containing 3 (NLRC3), an intracellular member of the NLR family, is a negative regulator of both immune cell modulation and tumor cell proliferation. However, the role of NLRC3 and the mechanisms underlying its effect on the tumor immune microenvironment remain unclear. In this study, we report that NLRC3 promotes antitumor immunity by specifically negatively regulating the infiltration and immunosuppressive function of monocytic myeloid-derived suppressor cells (M-MDSCs). Mechanistically, NLRC3 inhibits the stimulator of interferon genes (STING) signaling pathway, leading to reduced expression of programmed cell death ligand 1 (PD-L1) and CCR2 in M-MDSCs, thereby limiting the infiltration and immunosuppressive function of M-MDSCs. Notably, overexpression of NLRC3 in combination with the STING agonist c-GAMP significantly inhibited tumor growth. These findings reveal a critical role for NLRC3 in modulating the immune microenvironment and provide insights into the optimization of NLRC3-targeted therapeutics.
Insights
NLRC3 protein suppresses tumor growth by inhibiting immunosuppressive myeloid cells. This discovery offers new therapeutic strategies for cancer immunotherapy by targeting the NLRC3 STING pathway.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- NOD-like receptor (NLR) family CARD domain containing 3 (NLRC3) is an intracellular regulator of immune responses and tumor cell proliferation.
- The precise function of NLRC3 in the tumor immune microenvironment and its underlying mechanisms are not fully understood.
Purpose of the Study:
- To investigate the role of NLRC3 in antitumor immunity.
- To elucidate the mechanisms by which NLRC3 modulates the tumor immune microenvironment, particularly focusing on monocytic myeloid-derived suppressor cells (M-MDSCs).
Main Methods:
- Investigated NLRC3's effect on M-MDSC infiltration and immunosuppressive function.
- Examined the impact of NLRC3 on the stimulator of interferon genes (STING) signaling pathway.
- Assessed the expression of programmed cell death ligand 1 (PD-L1) and CCR2 in M-MDSCs.
- Evaluated tumor growth inhibition through NLRC3 overexpression and STING agonist (c-GAMP) treatment.
Main Results:
- NLRC3 was found to promote antitumor immunity by negatively regulating M-MDSC infiltration and function.
- NLRC3 inhibits the STING signaling pathway, reducing PD-L1 and CCR2 expression in M-MDSCs.
- This inhibition limits M-MDSC infiltration and their immunosuppressive activity within the tumor microenvironment.
- Combined overexpression of NLRC3 and administration of c-GAMP significantly suppressed tumor growth.
Conclusions:
- NLRC3 plays a crucial role in enhancing antitumor immunity by suppressing M-MDSCs.
- The NLRC3-STING pathway is a key regulator of the tumor immune microenvironment.
- Targeting NLRC3 presents a promising therapeutic strategy for optimizing cancer immunotherapy.