Abstract 6226: Single-cell analysis reveals clonally expanded CD57+ CD8 T cells in periphery are associated with response to PD-L1 blockade in bladder cancer patients
Authors: Yadav Mahesh , Fehlings Michael , Kim Leesun , Guan Xiangnan , Yuen Kobe C. , Tafazzol Alireza , Rishipathak Deepali , Sanjabi Shomyesh , Wallace Andrew , Nardin Alessandra , Ma Siming , Milojkovic Ana , Newell Evan , Mariathasan Sanjeev 
Published: June 2022

Abstract
The recent success of immune checkpoint blockade has revolutionized cancer treatment for many cancers, however, only a fraction of patients with advanced stages of cancers experience clinical benefit. Many studies have suggested that T cells against tumor neoantigens are critical mediators of response to checkpoint blockade. We showed previously that neoantigen-specific CD8 T cells in cancer patients responding to anti-PD-L1 (atezolizumab) therapy express high levels of CD57 and KLRG1. Here, we extended the study to bladder cancer patients treated with atezolizumab to identify predictive biomarkers of response. We immune profiled circulating CD8 T cells using multidimensional mass cytometry and single cell sequencing, and compared patients with objective response and progressive disease.
We found a higher frequency of CD57-expressing CD8 T cells at baseline in responding patients compared to patients who progressed during therapy (n=20, p&lt;0.01). High expression of CD57 was also observed in neoantigen-specific CD8 T cells in responding patients. These findings were corroborated in a validation cohort (n=30, p&lt;0.01) and notably, higher frequency of CD57+ T cells was only observed in patients responding to atezolizumab and not in patients responding to chemotherapy treatment (n=40). We further used single-cell transcriptomics, together with CITE-seq and paired TCR sequencing, to characterize CD57+ CD8 T cells in a subset of patients (n=16) and identified a cluster within CD57+ CD8 T cells, which was characterized by enrichment of genes associated with activation, cytotoxicity and tissue resident memory markers in responding patients. Compared to patients with progressive disease, there was an increased clonal expansion among CD57+ CD8 T cells at baseline in responders, which was driven specifically by the activated cluster. Furthermore, we found increased overlap between TCR repertoires of tumor-infiltrating T cells and CD57+CD8 T cells, compared to CD57- CD8 T cells in the periphery, suggesting that levels of CD57+ CD8 T cells in the periphery could be indicative of quality of anti-tumor T cell response.This study identified and confirmed that elevated levels of circulating CD8 T cells expressing CD57 are associated with response to atezolizumab in bladder cancer patients. These data provide evidence and rationale for an easily accessible blood-based biomarker for selecting patients for atezolizumab therapy.
Citation Format: Mahesh Yadav, Michael Fehlings, Leesun Kim, Xiangnan Guan, Kobe C. Yuen, Alireza Tafazzol, Deepali Rishipathak, Shomyesh Sanjabi, Andrew Wallace, Alessandra Nardin, Siming Ma, Ana Milojkovic, Evan Newell, Sanjeev Mariathasan. Single-cell analysis reveals clonally expanded CD57+ CD8 T cells in periphery are associated with response to PD-L1 blockade in bladder cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6226.