69OComprehensive profiling of genomic and TCR repertoire in localized stage lung adenocarcinomas from a prospective cohort study

Background: Recently, neoadjuvant targeted therapy and immunotherapy have presented a promising clinical effect for localized stage non-small cell lung cancer. However, the characteristics and relationship of genomic and immune profiling in surgical lung adenocarcinomas has been poorly delineated to date. Methods: We prospectively enrolled 100 consecutive patients with pulmonary nodule who intended to undergo curative lung resection during June 2017 to July 2018 (NCT03320044). We investigated the TCR repertoire using next-generation deep sequencing of the complementarity determining region 3 (CDR3) of the TCR β chain in the tissue and WBC samples. Target-capture deep sequencing of 1021 genes was used to detect genomic variations in both tissue and paired plasma samples. Results: EGFR (65.4%), TP53 (36.5%) and KRAS (11.5%) mutated most frequently. KRAS (84.6%) was enriched in mucinous adenocarcinoma. High invasive subtype and no ground-glass opacity status is more likely to be increasing tissue TMB (p = 0.0016, p = 0.0012), higher T-cell clonality (p = 0.05, p = 0.05), and more HLA-LOH event (p = 0.038, p = 0.035). A median of TNB was 2 neoantigens/Mb and showed positive relation with TMB (r = 0.97, p < 0.0001). EGFR-mutant co-occurring mutations were enriched TGF-beta, PI3K-Akt, hippo and Leukocyte trans-endothelial migration pathway (q < 0.05). Lower TCR clonality was shown in patients with EGFR mutation and co-occurring hippo or Leukocyte trans-endothelial migration pathway. Alterations in DNA damage response (DDR) pathways were observed in 15.8% patients, and these patients showed higher clonality (p = 0.03). 35.3%(24/68) ctDNA-positive were found in Stage I with a mean ctDNA abundance of 0.18% (ranged from 0.012 to 3.3%), which suggested the challenge of bTMB in biomarker study of early-stage LUAD. Analysis of TCR repertoire from available paired WBC showed no obvious characteristics. Conclusions: This is the first prospective study integrating the correlation of genomic alteration and T-cell receptor in localized surgical LUAD. Analysis of co-altered pathway of EGFR-mutant LUAD and immune microenviroment will provide a better understanding in choosing biomarkers and optimal benefit patients for neoadjuvant therapy. Clinical trial identification: NCT03320044. Legal entity responsible for the study: Jun Wang. Funding: National Natural Science Foundation of China (No.81602001). Disclosure: All authors have declared no conflicts of interest.