Single-cell analysis reveals clonally expanded tumor-associated CD57+ CD8 T cells are enriched in the periphery of patients with metastatic urothelial cancer responding to PD-L1 blockade
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ..
BACKGROUND: A growing body of evidence suggests that T-cell responses against neoantigens are critical regulators of response to immune checkpoint blockade. We previously showed that circulating neoantigen-specific CD8 T cells in patients with lung cancer responding to anti-Programmed death-ligand 1 (PD-L1) (atezolizumab) exhibit a unique phenotype with high expression of CD57, CD244, and KLRG1. Here, we extended our analysis on neoantigen-specific CD8 T cells to patients with metastatic urothelial cancer (mUC) and further profiled total CD8 T cells to identify blood-based predictive biomarkers of response to atezolizumab.
METHODS: We identified tumor neoantigens from 20 patients with mUC and profiled their peripheral CD8 T cells using highly multiplexed combinatorial tetramer staining. Another set of patients with mUC treated with atezolizumab (n=30) or chemotherapy (n=40) were selected to profile peripheral CD8 T cells by mass cytometry. Using single-cell transcriptional analysis (single-cell RNA sequencing (scRNA-seq)), together with CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing) and paired T-cell receptor (TCR) sequencing, we further characterized peripheral CD8 T cells in a subset of patients (n=16).
RESULTS: High frequency of CD57 was observed in neoantigen-specific CD8 T cells in patients with mUC responding to atezolizumab. Extending these findings to bulk CD8 T cells, we found higher frequency of CD57 expressing CD8 T cells before treatment in patients responding to atezolizumab (n=20, p<0.01) but not to chemotherapy. These findings were corroborated in a validation cohort (n=30, p<0.01) and notably were independent of known biomarkers of response. scRNA-seq analysis identified a clonally expanded cluster enriched within CD57+ CD8 T cells in responding patients characterized by higher expression of genes associated with activation, cytotoxicity, and tissue-resident memory markers. Furthermore, compared with CD57- CD8 T cells, TCRs of CD57+ CD8 T cells showed increased overlap with the TCR repertoire of tumor-infiltrating T cells.
CONCLUSIONS: Collectively, we show high frequencies of CD57 among neoantigen-specific and bulk CD8 T cells in patients responding to atezolizumab. The TCR repertoire overlap between peripheral CD57+ CD8 T cells and tumor-infiltrating lymphocytes suggest that accumulation of peripheral CD57+ CD8 T cells is reflective of an ongoing antitumor T-cell response. Our findings provide evidence and rationale for using circulating CD8 T cells expressing CD57 as a readily accessible blood-based biomarker for selecting patients with mUC for atezolizumab therapy.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:10 |
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| Enthalten in: |
Journal for immunotherapy of cancer - 10(2022), 8 vom: 14. Aug. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Fehlings, Michael [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 22.08.2022 Date Revised 10.09.2022 published: Print Citation Status MEDLINE |
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| doi: |
10.1136/jitc-2022-004759 |
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| Förderinstitution / Projekttitel: |
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NLM345003721 |
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| 100 | 1 | |a Fehlings, Michael |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Single-cell analysis reveals clonally expanded tumor-associated CD57+ CD8 T cells are enriched in the periphery of patients with metastatic urothelial cancer responding to PD-L1 blockade |
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| 500 | |a Date Revised 10.09.2022 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. | ||
| 520 | |a BACKGROUND: A growing body of evidence suggests that T-cell responses against neoantigens are critical regulators of response to immune checkpoint blockade. We previously showed that circulating neoantigen-specific CD8 T cells in patients with lung cancer responding to anti-Programmed death-ligand 1 (PD-L1) (atezolizumab) exhibit a unique phenotype with high expression of CD57, CD244, and KLRG1. Here, we extended our analysis on neoantigen-specific CD8 T cells to patients with metastatic urothelial cancer (mUC) and further profiled total CD8 T cells to identify blood-based predictive biomarkers of response to atezolizumab | ||
| 520 | |a METHODS: We identified tumor neoantigens from 20 patients with mUC and profiled their peripheral CD8 T cells using highly multiplexed combinatorial tetramer staining. Another set of patients with mUC treated with atezolizumab (n=30) or chemotherapy (n=40) were selected to profile peripheral CD8 T cells by mass cytometry. Using single-cell transcriptional analysis (single-cell RNA sequencing (scRNA-seq)), together with CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing) and paired T-cell receptor (TCR) sequencing, we further characterized peripheral CD8 T cells in a subset of patients (n=16) | ||
| 520 | |a RESULTS: High frequency of CD57 was observed in neoantigen-specific CD8 T cells in patients with mUC responding to atezolizumab. Extending these findings to bulk CD8 T cells, we found higher frequency of CD57 expressing CD8 T cells before treatment in patients responding to atezolizumab (n=20, p<0.01) but not to chemotherapy. These findings were corroborated in a validation cohort (n=30, p<0.01) and notably were independent of known biomarkers of response. scRNA-seq analysis identified a clonally expanded cluster enriched within CD57+ CD8 T cells in responding patients characterized by higher expression of genes associated with activation, cytotoxicity, and tissue-resident memory markers. Furthermore, compared with CD57- CD8 T cells, TCRs of CD57+ CD8 T cells showed increased overlap with the TCR repertoire of tumor-infiltrating T cells | ||
| 520 | |a CONCLUSIONS: Collectively, we show high frequencies of CD57 among neoantigen-specific and bulk CD8 T cells in patients responding to atezolizumab. The TCR repertoire overlap between peripheral CD57+ CD8 T cells and tumor-infiltrating lymphocytes suggest that accumulation of peripheral CD57+ CD8 T cells is reflective of an ongoing antitumor T-cell response. Our findings provide evidence and rationale for using circulating CD8 T cells expressing CD57 as a readily accessible blood-based biomarker for selecting patients with mUC for atezolizumab therapy | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a CD8-positive T-lymphocytes | |
| 650 | 4 | |a immunotherapy | |
| 650 | 4 | |a receptors, antigen | |
| 650 | 4 | |a urinary bladder neoplasms | |
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| 650 | 7 | |a CD57 Antigens |2 NLM | |
| 650 | 7 | |a Receptors, Antigen, T-Cell |2 NLM | |
| 700 | 1 | |a Kim, Leesun |e verfasserin |4 aut | |
| 700 | 1 | |a Guan, Xiangnan |e verfasserin |4 aut | |
| 700 | 1 | |a Yuen, Kobe |e verfasserin |4 aut | |
| 700 | 1 | |a Tafazzol, Alireza |e verfasserin |4 aut | |
| 700 | 1 | |a Sanjabi, Shomyseh |e verfasserin |4 aut | |
| 700 | 1 | |a Zill, Oliver A |e verfasserin |4 aut | |
| 700 | 1 | |a Rishipathak, Deepali |e verfasserin |4 aut | |
| 700 | 1 | |a Wallace, Andrew |e verfasserin |4 aut | |
| 700 | 1 | |a Nardin, Alessandra |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Siming |e verfasserin |4 aut | |
| 700 | 1 | |a Milojkovic, Ana |e verfasserin |4 aut | |
| 700 | 1 | |a Newell, Evan W |e verfasserin |4 aut | |
| 700 | 1 | |a Mariathasan, Sanjeev |e verfasserin |4 aut | |
| 700 | 1 | |a Yadav, Mahesh |e verfasserin |4 aut | |
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