Study On Immune Efficacy Prediction And Genomic Evolution Based On Concurrent Lung And Kidney Carcinoma

ObjectiveThe morbidity and mortality of lung cancer ranked first among malignant tumors,but double source cancer of lung and kidney is rare in the clinic and few studies have been reported.Although outstanding progress has been achieved in surgery,radiotherapy,chemotherapy and molecular targeted therapy,the 5-year survival rate of advanced lung cancer is still not satisfactory(4.7%),and the prognosis of patients with renal cell carcinoma is even worse.The application and splendid efficacy of immunosuppressive drugs represented by programmed cell death protein1(PD-1)and programmed death-ligand1(PD-L1)has increased the 5-year survival rate of patients with advanced lung cancer to 16%.However,only about 20% of lung cancer patients may be effective in immunotherapy.How to screen the dominant population become the focus of immunotherapy research.In addition,most patients may show immunotherapy resistance during the initial or late treatment.However,the mechanism of drug resistance in immunotherapy is complex and not fully elucidated.At present,there are limited longitudinal studies on tumor evolution,and few studies have explored how tumor cells reshape their genomes to avoid immune system attacks during immunotherapy.Therefore,this study will analyze the predictive indicators of the efficacy of immunotherapy and the changes of tumor cells before and after treatment at the gene level,and explore the predictive markers of immunotherapy and the mechanism of drug resistance to immunotherapy.MethodsWe collected three tissue samples from a patient with concurrent lung and kidney carcinoma,namely,pulmonary lesion(P),renal lesion(M1)and drug resistant renal lesion(M2).The curative effect was evaluated every 2 cycles until the disease progressed.The expression of PD-L1 in tumor samples was detected by immunohistochemical method(IHC).Samples obtained above were sequenced by whole-exome sequencing(WES),and matched peripheral blood was used as control.ResultsThe levels of tumor mutational burden(TMB)and tumor neoantigens burden(TNB)of P,M1,and M2 were not in conformity with the clinical efficacy.We found that the combination of biomarkers of human leukocyte antigen(HLA)associated with TNB and tumor heterogeneity is associated with immunotherapy response.Importantly,we identified the dynamic change in the copy number of HLA alleles,which may mediate the acquired resistance of M2 to PD-1 inhibitors.In addition,tracking genome evolution can depict the spatio-temporal heterogeneity between lung cancer and renal cell carcinoma,as well as between renal cell carcinoma and the potential drivers that promote the progression of renal cell carcinoma.In addition,we speculate the possible immunogenicity of new tumor antigens by constructing the evolutionary tree of neoantigens.Conclusions1.HLA genes totally absence may be closely associated with immunotherapy of acquired drug resistance,HLA correction TNB level may be more curative effect than single TNB level predictive value.2.Resistance to produce the genomics of change and the change of protein expression,may be late for drug research and development of guidance.