| Over the last decade,immune checkpoint blockade(ICB)as an epochal immunotherapy has achieved remarkable clinical effects in multiple types of cancers,becoming a new type of cancer treatment after traditional therapies such as surgery,chemotherapy and radiotherapy.Since programmed death 1(PD-1)inhibitor was approved by the United States Food and Drug Administration(FDA)for the treatment of head and neck squamous cell carcinoma(HNSCC)in 2016,blockade of PD-1/PD-L1 improves overall survival in HNSCC patients and becomes a firstline therapy in patients with recurrent and/or metastatic HNSCC.However,the overall response rate to blockade of PD-1/PD-L1 therapy in HNSCC is still less than 20%.Therefore,finding predictive biomarkers for ICB and exploring methods to improve the response rate to ICB of HNSCC have become the focus of current research.Tumor microenvironment(TME)has attracted more attention due to its close relationship with prognosis and response to ICB therapy in cancer patients.In many types of cancer,TME with high infiltration of CD8~~+T cell are associated with good clinical outcomes and better responses to ICB treatment.Major histocompatibility complex class I molecules(MHC-Ⅰ)can affect the type of TME due to their important role in antigen processing and presentation.As the regulatory role of long non-coding RNA(lncRNA)in tumor immunity has been gradually proven,it is particularly important to explore the relationship between lncRNA and MHC-Ⅰ for understanding the mechanism of response to ICB treatment.In addition,the information such as location and interaction of various immune cells in TME plays an important role in anti-tumor immunity.Therefore,tertiary lymphoid structure(TLS)formed by aggregation of various immune cells in TME has attracted more attention.Compared with TME with only CD8~~+T cell infiltration,TME with both the presence of TLS and CD8~~+T cell infiltration is associated with better prognosis and a high response rate to ICB treatment.However,the influence of TLS on the responsiveness to ICB treatment in HNSCC has not been clarified.Aiming at the above problems,this study intends to explore the correlation among MHC-Ⅰ related lncRNA,the prognosis in HNSCC and T cell infiltration in TME and the influence of intratumoral TLS on the prognosis in HNSCC and ICB treatment,which can further reveal the mechanism involving ICB response in HNSCC and find the methods improving the response rate to ICB treatment.Part oneStudy on the correlation between MHC-Ⅰ related lncRNA and prognosis and tumor-infiltrating T cells in HNSCCObjective:Deletion of major histocompatibility complex class I molecules(MHC-Ⅰ)is an important mechanism for immune evasion of head and neck squamous cell carcinoma(HNSCC)cancer cells,which can also determine the infiltration of immune cells in TME.Long non-coding RNA(lncRNA)have been shown to be involved in anti-tumor immune response and regulation,including antigen processing and presentation.However,the lncRNA regulation of MHC-Ⅰ expression in HNSCC and the influence of lncRNA on immune components of TME has not been studied yet.It is important to explore the relationship between MHC-Ⅰ related lncRNA and TME for understanding the ICB treatment response mechanism of HNSCC.Methods:TCGA database was used to screen the lncRNA co-associated with MHC-Ⅰ and prognosis in HNSCC patients.KEGG and GO enrichment analysis was used to reveal the potential biological functions of the relevant lncRNA.The expression of relevant lncRNA in HNSCC tissues and cell lines was verified by qRT-PCR.In situ hybridization(ISH)and multiplex immunohistochemistry(m IHC)were used to determine the correlation between lncRNA and the prognosis in HNSCC patients and the tumor-infiltrating T cells in HNSCC.Results:By mining TCGA database,lncRNA,LINC02195,which was simultaneously associated with MHC-Ⅰ and the prognosis in HNSCC patients,was screened out.qRT-PCR results showed that the expression of LINC02195 in HNSCC tissues and cell lines was higher than that in normal mucosae.KEGG and GO analysis showed that LINC02195 was closely associated with antigen processing and presentation.In a cohort of primary HNSCC patients,ISH results showed that high expression of LINC02195 was associated with good prognosis.The results from m IHC showed that the high expression of LINC02195 was associated with high densities of CD8~+and CD4~~+T cells in TME.Conclusions:Our results indicate that LINC02195 is an MHC-Ⅰ related lncRNA in HNSCC.High expression of LINC02195 predicts a favorable prognosis and high densities of CD8~+and CD4~~+T cells in TME.Part twoStudy on the effect of TLS in HPV-HNSCC prognosis and ICB treatmentObjective: As an unprecedented immunotherapy,immune checkpoint blockade(ICB)has been successfully used in cancer treatment.Currently,ICB therapy targeting PD-1/PD-L1 has been used for treatment of HNSCC.However,the overall response rate to blockade of PD-1/PD-L1 therapy in HNSCC is still less than 20%.Therefore,finding predictive biomarkers for ICB and exploring methods to improve the response rate to ICB of HNSCC have become the focus of current research.It has recently been reported that the appearance of intratumoral tertiary lymphoid structure(TLS)is associated with better prognosis and response to ICB treatment.However,the relationship between TLS and the prognosis in HPV-negative HNSCC(HPV-HNSCC)patients and the therapeutic effect of ICB is still unclear.To explore the effects of TLS on the prognosis of HNSCC patients and ICB treatment is helpful to further understand the mechanisms related to ICB treatment response of HNSCC,which can provide a new perspect for exploring ways to improve response rate to ICB treatment in HPV-HNSCC.Methods: By analyzing the TCGA-HNSCC dataset,the TME composition of each sample was clarified and classified.The characteristic immune cells and immune-related genes of each type were explored,combining the correlation with the prognosis in HNSCC patients.To investigate the correlation between TLS and prognosis in HPV-HNSCC patients and T cell infiltration,the tumor tissue samples from HPV-HNSCC patients were used.By modifying mouse HPV-HNSCC cell line,a mouse model of HPV-HNSCC with TLS infiltration was established to explore the effect of TLS on the PD-1 blockade treatment of HPV-HNSCC and its potential mechanism.Results: By analyzing the TCGA-HNSCC dataset,we developed a new immune classification for TME of HNSCC.We found that the TLS-enriched TME type had a better prognosis.By analyzing the patient cohort of primary HPV-HNSCC,we found that TLS was present in a part of tumor samples of HPV-HNSCC and was associated with the densities of DC-LAMP+ DC,CD4~+T cells,CD8~+T cells and TCF1+CD8~+T cells in TME.By overexpressing LIGHT in 4MOSC1 mouse HNSCC cell lines,we established the HPV-HNSCC mouse model with TLS infiltration.In the HPVHNSCC mouse model,we found that the presence of TLS in TME was associated with the high infiltration of DCs,CD8~+T cells as well as progenitor exhausted CD8~+T cells in TME,and showed a stronger response to PD-1 blockade therapy.Conclusions: Our study indicates that TLS plays an important role in the prognosis and anti-tumor immunity for HPV-HNSCC.Inducing TLS formation in HPVHNSCC tumor tissue is expected to be an effective method to improve ICB response rate in HPV-HNSCC patients. |
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