880 Quantification and localization of T cell clones in the in situ microenvironment of non-small cell lung cancer

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Background Tumor-specific T-cell activation and subsequent clonal expansion are essential for an effective anti-cancer immune response. Quantifying this clonal expansion in patient cancer samples might provide prognostic and predictive information in highly immunogenic tumors like non-small cell lung cancer (NSCLC). The aim of this study was to characterize TCR clonality in the tumor microenvironment of NSCLC patients, its relation to immune cell compositions, and its association with clinical parameters. Methods We determined the α/β TCR clonality using RNA sequencing data from fresh frozen tumor tissue of 182 NSCLC patients. Clonality metrics were presented as Gini index and associated with molecular data (RNAseq and targeted DNAseq) and spatial immune cell profiles from extensive immunohistochemical and multiplex immunofluorescence. The identified TCR clones were localized by in situ sequencing in three individual patient cancer samples. Results The analysis revealed a broad spectrum of TCR clonality patterns, ranging from high T-cell clone diversity and high evenness (low Gini index) to clonal dominance with low evenness (Gini index high). TCR clonality in cancer tissue was lower than in matched normal lung parenchyma (p = 0.021). The Gini index was not associated with histological subtypes or patient survival but correlated strongly with distinct mutations (EGFR, P53) and estimated tumor mutation burden (p<0.001). Gene expression analysis indicated that high TCR clonality was connected to an inflamed tumor phenotype (high mRNA: PRF1, GZMA, GZMB, INFG) with an exhaustion signature (high mRNA: LAG3, TIGIT, IDO1, PD-1, PD-L1). Correspondingly, immune cells positive for PD-1+, CD3+, CD8A+, CD163+, and CD138+ infiltrated cancer tissue with high clonality. In situ sequencing of patients’ cancer tissue samples revealed that dominant T cell clones tended to be in close vicinity to tumor cells. Finally, in an NSCLC cohort with checkpoint inhibitor-treated patients, high TCR clonality was associated with higher response (p = 0.016) and prolonged overall survival (p = 0.003, median survival 2.9 vs 13.8 months). Conclusions Our study indicates that T-cell expansion is directly related to genotypes and immune phenotypes in individual cancer samples. The link between TCR clonality and immunotherapy outcomes confirms its functional significance and suggests strong biomarker potential. Ethics Approval This study was conducted in concordance with the Declaration of Helsinki and the Swedish Ethical Review Act (approved by the Ethical Review Board in Uppsala, #2012/532).

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