Abstract 3222: The sharing of T cell clones in peripheral CD8+PD-1+ T cells with TILs is a novel biomarker predicting the efficacy of anti-PD-L1 therapy
Authors: Jiefei Han, Zhijie Wang, Yuqi Wang, Si Chen, Hua Bai, Jianchun Duan, Jie Wang
Journal: Cancer Research (2019)

Abstract Background: The optimal biomarker to select suitable patients for immune checkpoint blockades (ICBs) therapy remains to be well established. The dynamic variations of molecular alterations during ICBs treatment need to be better understood. Here,we explored a novel biomarkerbased on T cell receptor (TCR) repertoire (TcR) and traced the variations during PD-L1 blockade delivery.Methods:Patients treated with anti-PD-L1 clinical trials were enrolled in this pilot study (n=21). Next-generation sequencing (NGS) was performed to assess molecular tumor burden index (mTBI) based on a 1021 gene panel, for genomic DNA from tumor tissue and cfDNA. Multiple PCR and NGS on the CDR3 region of TCR beta chain was used to reflect the distribution of T cell clones in TILs and peripheral CD8+PD1+ T cells. We applied gene altation data combined with each patient’s major histocompatibility complex (MHC) class I haplotype in a neoantigen prediction platform that evaluates binding affinities of somatic peptides to class I MHC, antigen processing, and self-similarity. Neoantigen peptides were synthesis and used to stimulate Peripheral blood mononuclear cell(PBMC)from the same patient. The expression of OX-40 and 4-1BB were anylisied by flow cytometry to determine activity change of stimulated T cells. Results: A number of T cell clones (1-24) in TILs were shared in peripheral CD8+PD1+ T cells. The total ratio of shared clones to top 100 clones in TILs ranged from 0.00% to 31.35%, while the mean ratio of each shared clone was 1.24% (0.00% to 3.18%). Patients responding to anti-PD-L1 therapy showed higher mean ratio of shared clonesthan non-responding ones (1.76% vs. 0.85%; P= 0.012), our further analysis showed the progression free survival (PFS) is also longer in patients with higher mean ratio of shared clones (P=0.022). Intriguingly, the ratio of shared clones to total CD8+PD1+ T cell clones of peripheral blood showed synchronized change consistent with mTBI and tumor burden. PBMC stimulated by neoantigen peptide expressed higher OX-40 and 4-1BB than control. Further TCR sequencing performed on stimulated T cells showed consistency with shared clone at baseline. Conclusion: The high mean ratio of shared clones in TILs is a potential and promising biomarker to predict the efficacy of ICBs therapy and reflect the target T lymphocytes variations during the treatment, which warrants the further validation in large cohort. Note: This abstract was not presented at the meeting. Citation Format: Jiefei Han, Zhijie Wang, Yuqi Wang, Si Chen, Hua Bai, Jianchun Duan, Jie Wang. The sharing of T cell clones in peripheral CD8+PD-1+ T cells with TILs is a novel biomarker predicting the efficacy of anti-PD-L1 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3222.