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ACAP1 Deficiency Predicts Inferior Immunotherapy Response in Solid Tumors
Qiyi Yi1, Youguang Pu2, Fengmei Chao2
1School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei 230032, China.
Background:
ACAP1 plays a key role in endocytic recycling, which is essential for the normal function of lymphocytes. However, the expression and function of ACAP1 in lymphocytes have rarely been studied.
Methods:
Large-scale genomic data, including multiple bulk RNA-sequencing datasets, single-cell sequencing datasets, and immunotherapy cohorts, were exploited to comprehensively characterize ACAP1 expression, regulation, and function. Gene set enrichment analysis (GSEA) was used to uncover the pathways associated with ACAP1 expression. Eight algorithms, including TIMER, CIBERSORT, CIBERSORT-ABS, QUANTISEQ, xCELL, MCPCOUNTER, EPIC, and TIDE, were applied to estimate the infiltrating level of immune cells. Western blotting, qPCR, and ChIP-PCR were used to validate the findings from bioinformatic analyses. A T-cell co-culture killing assay was used to investigate the function of ACAP1 in lymphocytes.
Results:
ACAP1 was highly expressed in immune-related tissues and cells and minimally in other tissues. Moreover, single-cell sequencing analysis in tumor samples revealed that ACAP1 is expressed primarily in tumor-infiltrating lymphocytes (TILs), including T, B, and NK cells. ACAP1 expression is negatively regulated by promoter DNA methylation, with its promoter hypo-methylated in immune cells but hyper-methylated in other cells. Furthermore, SPI1 binds to the ACAP1 promoter and positively regulates its expression in immune cells. ACAP1 levels positively correlate with the infiltrating levels of TILs, especially CD8+ T cells, across a broad range of solid cancer types. ACAP1 deficiency is associated with poor prognosis and immunotherapeutic response in multiple cancer types treated with checkpoint blockade therapy (ICT). Functionally, the depletion of ACAP1 by RNA interference significantly impairs the T cell-mediated killing of tumor cells.
Conclusions:
Our study demonstrates that ACAP1 is essential for the normal function of TILs, and its deficiency indicates an immunologically "cold" status of tumors that are resistant to ICT.
Insights
ACAP1 is crucial for tumor-infiltrating lymphocytes (TILs) function and anti-tumor immunity. Its deficiency in cancer indicates poor prognosis and resistance to immunotherapy.
Area of Science:
- Immunology
- Molecular Biology
- Cancer Research
Background:
- Lymphocyte function relies on endocytic recycling, a process involving ACAP1.
- The expression and role of ACAP1 in lymphocytes remain largely unexplored.
Purpose of the Study:
- To comprehensively analyze ACAP1 expression, regulation, and functional significance in lymphocytes and cancer.
Main Methods:
- Utilized large-scale genomic data (RNA-seq, single-cell sequencing) and immunotherapy cohorts.
- Employed bioinformatics (GSEA, immune cell infiltration algorithms) and experimental validation (Western blot, qPCR, ChIP-PCR, T-cell killing assays).
Main Results:
- ACAP1 is highly expressed in immune cells, particularly in tumor-infiltrating lymphocytes (TILs).
- ACAP1 expression is regulated by DNA methylation and positively influenced by SPI1 binding.
- Elevated ACAP1 correlates with increased TILs (especially CD8+ T cells) and predicts better response to immune checkpoint blockade therapy (ICT).
- ACAP1 depletion impairs T-cell mediated tumor cell killing.
Conclusions:
- ACAP1 is vital for TIL function and anti-tumor immunity.
- ACAP1 deficiency is linked to an immunologically "cold" tumor phenotype and resistance to ICT.
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