| Immune checkpoint inhibitor(ICI)therapy has revolutionized the treatment of many cancers.However,the limited population that benefits from ICI therapy makes it necessary to screen predictive biomarkers for stratifying patients.Currently,many biomarkers,such as tumor mutational burden(TMB),have been used in the clinic as indicative biomarkers.However,some high-TMB patients with mutations in genes that are closely related to immunotherapeutic resistance are not sensitive to ICI therapy.Thus,there is a need to move beyond TMB and identify specific genetic determinants of the response to ICI therapy.In this study,we established a comprehensive mutation-based gene set across different tumor types to predict the efficacy of ICI therapy,and explored the relationship between NOTCH4 mutation and the response to ICI treatment.ICI therapy has the potential to induce durable responses,but current ICI therapy alone can only benefit some patients.The etiology of primary and secondary resistance to ICI therapy is multifaceted,not only from tumor-intrinsic factors but also from complex interactions between cancer and its microenvironment.Tumor angiogenesis and the immune microenvironment are two essential aspects of the tumor microenvironment(TME).The combination of receptor tyrosine kinase(RTK)inhibitor(TKI)-mediated antiangiogenic therapy and CD8 T lymphocyte-mediated immunotherapy has become an important focus of cancer treatment,with good results in many tumor types.However,the complex regulatory interactions between the two treatment strategies have not been elucidated.Therefore,we systematically investigated the association between RTKs and CD8 T lymphocyte genes(CD8Ts)across cancers.This paper consists of the following three parts:(1)The first part of the study is that an eleven-gene mutation-based gene set was generated to divide patients into a high-risk group and a low-risk group in a training cohort(1572 patients with 9 types of cancers who were treated with ICI therapy).The prognosis and immune response in the low-risk group were significantly higher than those in the high-risk group.The validation was performed in a validation cohort(932 patients with 5 types of cancers who were treated with ICI therapy).Mutations in these 11 genes were associated with a better response to ICI therapy.In addition,the mutation-based gene set was demonstrated to be an independent prognostic factor after ICI therapy.We further explored the role of the immune context in determining the benefits of immunotherapy in 10,143 patients with 33 types of cancers and found distinct immune landscapes for the high-and low-risk groups.In terms of tumor-extrinsic immune responses,the low-risk group was characterized by higher abundance of immune cells,higher TCR and BCR diversity,and higher chemokine expression.In terms of tumor-intrinsic immune responses,the low-risk group had significantly higher mutational burden and neoantigen burden than the high-risk group,suggesting that the low-risk group was more immunogenic.The high-risk group exhibited higher CNV burden and aneuploidy compared with the low-risk group,which is consistent with previous finding that tumor aneuploidy is associated with reduced response to immunotherapy and immune evasion.The expression of MHC-I and MHC-II-related antigen-presenting molecules was higher in the low-risk group.Focal amplifications of immune checkpoint genes,such as PD-L1(9p24.1)and PD-L2(9p24.1),were observed in the low-risk group,and the mRNA expression of PD-L1 and PD-L2 were also significantly increased in the low-risk group.(2)In the second part of the study,in an ICI-treated cohort(n=662),we found that patients with NOTCH4 mutation had better clinical benefits in terms of objective response rate(ORR:42.9%vs 25.9%,P=0.007),durable clinical benefit(DCB:54.0%vs 38.1%,P=0.021),progression-free survival(PFS,hazard ratio[HR]=0.558,P<0.001),and overall survival(OS,HR=0.568,P=0.006).In addition,we validated the prognostic value of NOTCH4 mutation in an independent ICI-treated cohort(n=1423).Based on multiomics data,we found that NOTCH4 mutation is significantly associated with enhanced immunogenicity,including a high TMB,the high expression of costimulatory molecules,and activation of the antigen-processing machinery,and NOTCH4 mutation positively correlates activated antitumor immunity,including high levels of immune cell infiltration and high expression of chemokines.(3)The third part of the study found that RTKs exhibited extensive genetic alterations across cancers,and are significantly related to the activity of cancer hallmark-related pathways.We identified crosstalk between RTKs and CD8Ts.Four crosstalk patterns were determined,and a scoring system was established to evaluate crosstalk patterns for individual patients.The high crosstalk score subtype was associated with significant clinical benefits and characterized by immune activation.Two immunotherapy cohorts confirmed that patients with high crosstalk scores had an inflamed TME phenotype and significant therapeutic advantages.In conclusion,the mutation-based gene set constructed in this project can accurately predict the prognosis of cancer patients with ICI treatment,and the determinization of the relationship between the internal and external immune response mechanisms with the efficacy of different subgroups of patients,which will help to make immunotherapy decisions for cancer patients,have good promotion and clinical translation potential,and be of great practical significance for the realization of precise tumor immunotherapy.At the same time,this study found that NOTCH4 mutation is a novel biomarker for predicting response to ICI therapy and is associated with better response to ICI therapy.Finally,this study found crosstalk between RTK and CD8T,indicating that anti-angiogenic-based targeted therapy combined with immune checkpoint inhibitor-based immunotherapy can work synergistically in tumor treatment,which provides a theoretical basis for target-immune combination therapy. |
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