Abstract 2230: Diversity of peripheral CD8+PD-1+ T cells is a novel predictive biomarker for response to anti-PD-1 antibody treatment in lung cancer patients
Authors: Matsumoto Seiji , Matsutani Takaji , Fujita Yoshiko , Kitaura Kazutaka , Nakamichi Tohoru , Nakamura Akifumi , Kuroda Ayumi , Hashimoto Masaki , Kondo Nobuyuki , Suzuki Ryuji , Hasegawa Seiki 
Published: August 2019

Abstract
Background: Anti-PD-1 antibodies (nivolumab) are effective in the treatment of many cancers, including malignant melanoma, non-small cell lung cancer (NSCLC), renal cell cancer, and head and neck squamous cell carcinoma. Immune checkpoint inhibitors (ICIs) are only effective in around 20% of patients, which saw a demand for the development of biomarkers that predict a therapeutic response before administering treatment. As the biomarkers intratumoral PD-L1 expression and tumor mutation burden (TMB) both require tumor tissue biopsy, there is now a demand for safer and less invasive biomarkers. Peripheral and tumor CD8+PD-1+ T cells share neoantigen-specific T-cell receptors (TCRs), and are presumed to act as effector T cells with an antitumor effect at the tumor site. We analyzed the diversity in terms of TCR α and β repertoires on peripheral CD8+PD-1+ T cells and examined the relationship between this diversity and therapeutic effect of nivolumab.
Methods: This study used patients administered nivolumab after exhibiting no response to chemotherapy for recurrence following surgery. Peripheral blood mononuclear cells were collected from patients before administration of nivolumab. CD8+PD-1+ T cells were subjected to FACS sorting, NGS-based TCR repertoire analysis was performed by Repertoire Genesis Inc., and TCR diversity was evaluated statistically. CT scan was performed during week 12 of treatment and used to determine response to nivolumab. This study was approved by the Ethical Committee of Hyogo College of Medicine.
Results: Six of 12 patients responded to treatment. Upon comparing these responders (CR, PR) with non-responders (SD, PD), there were no differences in the proportion of PD-1+ in CD8+ T cells and the proportion of CD8+PD-1+ T cells in gated lymphocytes. TCR α diversity was significantly higher among responders than non-responders based on Shannon index, Simpson index and DE50 (P &lt; 0.05, P &lt; 0.05, P &lt; 0.01, respectively). TCR β diversity was also significantly higher among responders than non-responders based on Shannon index, Simpson index and DE50 (all P &lt; 0.01). Progression-free survival (PFS) was 371 days for responders and 148 days for non-responders. Overall survival (OS) was 633 days for responders and 308 days for non-responders, showing a significant difference between the groups.
Conclusion: TCR repertoire analysis was performed on CD8+PD-1+ T cells in easily-obtainable peripheral blood before nivolumab treatment in patients with NSCLC, and nivolumab was observed to be effective in patients with high TCR diversity. This result indicates the TCR diversity of peripheral CD8+PD-1+ T cells is effective as a predictive biomarker for response to ICI therapy. In the future, we intend to analyze TMB and neoepitopes using surgical specimens of these patients and determine the efficacy of this biomarker for cancers other than NSCLC.
Citation Format: Seiji Matsumoto, Takaji Matsutani, Yoshiko Fujita, Kazutaka Kitaura, Tohoru Nakamichi, Akifumi Nakamura, Ayumi Kuroda, Masaki Hashimoto, Nobuyuki Kondo, Ryuji Suzuki, Seiki Hasegawa. Diversity of peripheral CD8+PD-1+ T cells is a novel predictive biomarker for response to anti-PD-1 antibody treatment in lung cancer patients [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 2230.