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Experimental Metastasis and CTL Adoptive Transfer Immunotherapy Mouse Model
Published on: November 26, 2010
ATAD2 drives immunotherapy resistance by promoting lactic acid-mediated CD8+ T cell dysfunction in lung
Wanfeng Gao1, Jialei Xu1, Yue Li2
1State Key Laboratory of Medicinal Chemical Biology, Institute of Immunology, College of Life Sciences, Nankai University, Tianjin, China.
Background:
T cell-based immunotherapies have improved outcomes in lung adenocarcinoma (LUAD), yet many patients develop primary or acquired resistance. Tumor-intrinsic mechanisms that suppress CD8+ T cell function remain incompletely understood.
Methods:
Public LUAD transcriptomic datasets were analyzed to assess the association of ATPase family AAA domain-containing protein 2 (ATAD2) with prognosis and immune infiltration. Atad2-deficient LUAD cell lines were generated using CRISPR/Cas9 and co-cultured with activated CD8+ T cells to evaluate cytotoxicity, cytokine production, PD-1 expression and survival. The mediating role of lactic acid (LA) was confirmed using conditioned medium exposure, exogenous LA supplementation, and LDHA overexpression rescue experiments. ATAD2-mediated transcriptional regulation of LDHA was investigated by ChIP-qPCR and c-Myc overexpression. Subcutaneous tumor models were used to determine the effects of Atad2 deletion on LA accumulation, CD8+ T cell infiltration, tumor growth, and response to anti-PD-1 therapy.
Results:
ATAD2 was significantly upregulated in LUAD and correlated with poor survival and decreased CD8+ T cell infiltration. Atad2 deletion enhanced CD8+ T cell function and survival, effects reversed by exogenous LA. Mechanistically, ATAD2 enhanced c-Myc-dependent LDHA transcription, leading to increased lactic acid production and an immunosuppressive microenvironment. LDHA overexpression restored LA levels and reversed the immune-activating effects of Atad2 loss. In vivo, Atad2 deficiency reduced intratumoral LA, remodeled the immunosuppressive microenvironment, increased CD8+ T cell infiltration, inhibited tumor growth, and improved sensitivity to anti-PD-1 therapy.
Conclusions:
ATAD2 drives immunotherapy resistance in LUAD by activating an ATAD2-LDHA-LA axis that impairs CD8+ T cell function. Targeting ATAD2 may broadly restore antitumor immunity and enhance the efficacy of T cell-based immunotherapies.
Insights
ATPase family AAA domain-containing protein 2 (ATAD2) promotes lung adenocarcinoma (LUAD) immunotherapy resistance by increasing lactic acid, which suppresses CD8+ T cells. Targeting ATAD2 may enhance T cell therapies.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- T cell-based immunotherapies show promise for lung adenocarcinoma (LUAD).
- Primary or acquired resistance limits treatment efficacy in many LUAD patients.
- Tumor-intrinsic mechanisms suppressing CD8+ T cell function are not fully understood.
Purpose of the Study:
- To investigate the role of ATPase family AAA domain-containing protein 2 (ATAD2) in LUAD and its impact on T cell-mediated immunity.
- To elucidate the mechanisms by which ATAD2 influences the tumor microenvironment and immunotherapy response.
Main Methods:
- Analysis of public LUAD transcriptomic datasets to correlate ATAD2 expression with prognosis and immune infiltration.
- CRISPR/Cas9 generation of Atad2-deficient LUAD cell lines for in vitro co-culture assays with CD8+ T cells.
- Assessment of cytotoxicity, cytokine production, PD-1 expression, and cell survival.
- Investigation of the mediating role of lactic acid (LA) and lactate dehydrogenase A (LDHA) using conditioned medium, LA supplementation, and LDHA overexpression.
- In vivo studies using subcutaneous tumor models to evaluate the effects of Atad2 deletion on LA accumulation, CD8+ T cell infiltration, tumor growth, and anti-PD-1 therapy response.
Main Results:
- ATAD2 was significantly upregulated in LUAD, correlating with poor survival and reduced CD8+ T cell infiltration.
- Atad2 deletion enhanced CD8+ T cell function and survival, an effect reversed by exogenous LA.
- ATAD2 promotes LDHA transcription via c-Myc, increasing LA production and creating an immunosuppressive microenvironment.
- In vivo, Atad2 deficiency decreased intratumoral LA, increased CD8+ T cell infiltration, inhibited tumor growth, and improved anti-PD-1 therapy sensitivity.
Conclusions:
- ATAD2 drives LUAD immunotherapy resistance through an ATAD2-LDHA-LA axis that impairs CD8+ T cell function.
- Targeting ATAD2 presents a potential strategy to restore antitumor immunity and enhance T cell-based immunotherapy efficacy in LUAD.
