1.Multi-omics Analysis Unravels The Underlying Mechanisms Of Poor Prognosis And Differential Therapeutic Responses Of Solid Predominant Lung Adenocarcinoma 2.Study On The Heterogeneity Of Tumor Immune Microenvironment In Different Co-mutation Subtypes Of

Background:Solid predominant adenocarcinoma(SPA)has been reported to be a subtype with poor prognosis and unsatisfactory response to chemotherapy and targeted therapy in lung adenocarcinoma(LUAD).However,the underlying mechanisms remain largely unknown and the suitability of immunotherapy for SPA has not been investigated.Methods:We conducted a multi-omics analysis of 1078 untreated LUAD patients with clinicopathologic,genomic,transcriptomic,and proteomic data from both public and internal cohorts to determine the underlying mechanisms of poor prognosis and differential therapeutic responses of SPA and to investigate the potential of immunotherapy for SPA.The suitability of immunotherapy for SPA was further confirmed in a cohort of LUAD patients who received neoadjuvant immunotherapy in our center.Results:Along with its aggressive clinicopathologic behaviors,SPA had significantly higher tumor mutation burden(TMB)and number of pathways altered,lower TTF-1 and Napsin-A expression,higher proliferation score and a more immunoresistant microenvironment than non-solid predominant adenocarcinoma(Non-SPA),accounting for its worse prognosis.Additionally,SPA had significantly lower frequency of therapeutically targetable driver mutations and higher frequency of EGFR/TP53 comutation which was related to resistance to EGFR tyrosine kinase inhibitors,indicating a lower potential for targeted therapy.Meanwhile,SPA was enriched for molecular features associated with poor response to chemotherapy(higher chemoresistence signature score,lower chemotherapy response signature score,hypoxic microenvironment,and higher frequency of TP53 mutation).Instead,muti-omics profiling revealed that SPA had stronger immunogenicity and was enriched for positive biomarkers for immunotherapy(higher TMB and T cell receptor diversity;higher PD-L1 expression and more immune cell infiltration;higher frequency of gene mutations predicting efficacious immunotherapy,and elevated expression of immunotherapy-related gene signatures).Furthermore,in the cohort of LUAD patients who received neoadjuvant immunotherapy,SPA had higher pathological regression rates than Non-SPA and patients with major pathological response were enriched in SPA,confirming that SPA was more prone to respond to immunotherapy.Conclusions:Multi-omics analysis showed that SPA was enriched for molecular features associated with poor prognosis and unsatisfactory response to chemotherapy and targeted therapy,as compared with Non-SPA,which explained why SPA had worse survival and poor response to chemotherapy and targeted therapy.Besides,biomarkers for good response to immunotherapy were also enriched in SPA,indicating that it was more suitable to receive immunotherapy.Meanwhile,analysis of the cohort of LUAD patients who received neoadjuvant immunotherapy confirmed that SPA had better response to immunotherapy than Non-SPA.Background:KRAS mutation is the most common oncogenic alteration in lung adenocarcinoma(LUAD).Increasing evidence indicates that KRAS-mutant LUAD is a heterogeneous disease with a high frequency of co-occurring genomic alterations.Different co-mutation subtypes have distinct biology and therapeutic vulnerabilities.In this study,we aimed to investigate the impact of co-mutations on the efficacy of immunotherapy and tumor immune microenvironment in KRAS-mutant LUAD.Methods:KRAS-mutant LUADs were categorized into three subgroups according to the co-occurring genomic alterations:KSK subgroup(with STK11 or KEAP1 co-mutation and without TP53 co-mutation),KO subgroup(without STK11,KEAP1 or TP53 co-mutation),KP subgroup(with TP53 co-mutation).The impact of co-mutations on the efficacy of immunotherapy in KRAS-mutant LUAD was investigated in a tissue-based sequencing cohort(tNGS cohort,n=491)and a blood-based sequencing(bNGS cohort,n=30).The Cancer Genome Atlas(TCGA)LUAD database was used to explore the impact of comutations on the tumor immune microenvironment of KRAS-mutant LUAD,which was further validated in a LUAD cohort form our center based on immunohistochemistry.Results:KSK subgroup had significantly inferior progression-free survival(PFS)and overall survival(OS)as compared with KO subgroup and KP subgroup in both tNGS cohort(PFS:KSK vs KO,P<0.001;KSK vs KP,P<0.001;OS:KSK vs KO P<0.001;KSK vs KP P<0.001)and bNGS cohort(PFS:KSK vs KO,P=0.015;KSK vs KP,P=0.001;OS:KSK vs KO,P=0.182;KSK vs KP,P=0.013).Immunogenomic profiling and immune cell enrichment analyses revealed that there were significant differences in immunogenomic features and immune cell infiltration among three co-mutation subtypes,with low immune cell infiltration in KSK subgroup and high immune cell infiltration in KP subgroup.Conclusions:Co-mutations significantly affect the efficacy of immunotherapy and tumor immune microenvironment in KRAS-mutant LUAD.KSK subgroup had an immune-cold microenvironment and poor response to immunotherapy.