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Rescue of NLRC5 expression restores antigen processing machinery in head and neck cancer cells lacking functional
Brendan L C Kinney1,2, Sreenivasulu Gunti3, Vikash Kansal1,2
1Department of Otolaryngology - Head and Neck Surgery, Head and Neck Cancer Program, Winship Cancer Institute, Emory University School of Medicine, 550 Peachtree Street NE, 11Th Floor Otolaryngology, Atlanta, GA, 30308, USA.
Abstract:
The antigen processing machinery (APM) components needed for a tumor cell to present an antigen to a T cell are expressed at low levels in solid tumors, constituting an important mechanism of immune escape. More than most other solid tumors, head and neck squamous cell carcinoma (HNSCC) cells tend to have low APM expression, rendering them insensitive to immune checkpoint blockade and most other forms of immunotherapy. In HNSCC, this APM deficiency is largely driven by high levels of EGFR and SHP2, leading to low expression and activation of STAT1; however, recent studies suggest that p53, which is often mutated in HNSCCs, may also play a role. In the current study, we aimed to investigate the extent to which STAT1 and p53 individually regulate APM component expression in HNSCC cells. We found that in cells lacking functional p53, APM expression could still be induced by interferon-gamma or DNA-damaging chemotherapy (cisplatin) as long as STAT1 expression remained intact; when both transcription factors were knocked down, APM component expression was abolished. When we bypassed these deficient pathways by rescuing the expression of NLRC5, APM expression was also restored. These results suggest that dual loss of functional STAT1 and p53 may render HNSCC cells incapable of processing and presenting antigens, but rescue of downstream NLRC5 expression may be an attractive strategy for restoring sensitivity to T cell-based immunotherapy.
Insights
Head and neck squamous cell carcinoma (HNSCC) cells evade immune detection due to low antigen processing machinery (APM) expression. Restoring NLRC5 expression may re-sensitize HNSCC to immunotherapy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Solid tumors, particularly head and neck squamous cell carcinoma (HNSCC), exhibit low antigen processing machinery (APM) component expression, a key mechanism for immune evasion.
- This APM deficiency in HNSCC is linked to high EGFR and SHP2 levels, resulting in reduced STAT1 activity, and potentially influenced by p53 mutations.
Purpose of the Study:
- To investigate the individual roles of STAT1 and p53 in regulating APM component expression within HNSCC cells.
- To explore potential therapeutic strategies for overcoming immune evasion in HNSCC.
Main Methods:
- Utilized HNSCC cell lines with varying STAT1 and p53 functional status.
- Assessed APM component expression following interferon-gamma or cisplatin treatment.
- Investigated the impact of STAT1 and p53 knockdown on APM expression.
- Examined the effect of NLRC5 expression rescue on APM restoration.
Main Results:
- APM expression remained inducible by interferon-gamma or cisplatin in p53-deficient cells if STAT1 was present.
- Complete abolition of APM component expression occurred upon knockdown of both STAT1 and p53.
- Restoring NLRC5 expression successfully rescued APM component expression, bypassing the deficient STAT1/p53 pathways.
Conclusions:
- Dual loss of functional STAT1 and p53 significantly impairs HNSCC's ability to process and present antigens.
- Restoring NLRC5 expression presents a promising strategy to enhance HNSCC sensitivity to T cell-based immunotherapies.
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