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Abstract
Background Tumor plasticity constitutes a critical determinant of drug resistance and cancer recurrence, encompassing epithelial-mesenchymal transition (EMT), stemness, and onco-fetal reprogramming. Additionally, EMT serves as a pivotal driver of tumor immune evasion. FOLR1(folate receptor 1), a folate receptor protein, has been observed to be up-regulated in CRC patients with poor prognosis. This research investigates the mechanism by which FOLR1 promotes tumor plasticity and immune evasion in CRC.
Methods CRC tissues and adjacent normal tissues were used to study the FOLR1 expression level and its correlation with CRC progression and immune evasion. In vitro experiments using CRC cell lines, as well as subcutaneous and CRC liver metastasis models, confirmed that FOLR1 can enhance CRC plasticity. Flow cytometry, OT1-OVA system, tissue micro-arrays and RNA-seq of subcutaneous tumors confirmed the correlation between FOLR1 expression and antigen presentation. Multi-omic sequencing including RNA-seq, global lactylome and proteomics analysis were employed to unravel the molecular mechanisms of FOLR1. The correlation between Kla-STAT1 and p-STAT1 was studied using IP-WB, flow cytometry and immunofluorescence.
Results FOLR1 was abnormally overexpressed in CRC tissues and correlated with poor prognosis (IDDF2024-ABS-0280-Figure 1. The expression and clinical significance of FOLR1 in CRC). Functional experiments have preliminarily demonstrated that FOLR1 enhances CRC plasticity (IDDF2024-ABS-0280-Figure 2. FOLR1 promotes CRC tumorigenicity, IDDF2024-ABS-0280 Figure 3. FOLR1 enhances CRC plasticity) while promoting immune evasion (IDDF2024-ABS-0280 Figure 4. FOLR1 suppresses antigen presentation and affects cytotoxic T-cell activation and function). Further investigation into its molecular mechanism revealed that FOLR1 promotes lactate production in CRC cells by enhancing glycolysis, leading to the up-regulation of lactylation modification of STAT1 protein (IDDF2024-ABS-0280-Figure 5. FOLR1 increases lactylation levels in CRC cells through up-regulating glycolysis signaling). STAT1 lactylation antagonizes its phosphorylation, thereby inhibiting STAT1 activity and function (IDDF2024-ABS-0280-Figure 6. FOLR1 increased the plasticity and immune evasion of CRC via promoting stat1 lactylation). As a potent transcription factor regulating immune response and tumor survival, STAT1 lactylation led to the down-regulation of MHCI and up-regulation of c-MYC expression, thus promoting tumor immune evasion and enhancing tumor plasticity. FOLR1-ADC drugs in combination with immune checkpoint blockade (ICB) such as PD-1 will be applied in humanized CRC PDX mouse models to assess the feasibility of potential new therapeutic strategies.
The expression and clinical significance of FOLR1 in CRC
FOLR1 promotes CRC tumorigenicity
FOLR1 enhances CRC plasticity
FOLR1 suppresses antigen presentation and affects cytotoxic T-cell activation and function
FOLR1 increases lactylation levels in CRC cells through up-regulating glycolysis signaling
FOLR1 increased the plasticity and immune evasion of CRC via promoting stat1 lactylation
Conclusions These evidence demonstrated that FOLR1 promotes CRC plasticity and immune evasion via up-regulating STAT1 protein lactylation. Targeting FOLR1 in combination with ICB provides new treatment strategies for CRC.