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Exhausted intratumoral Vδ2- γδ T cells in human kidney cancer retain effector function
Chiara Rancan1, Marcel Arias-Badia1, Pranay Dogra2
1Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, CA, USA.
Abstract:
Gamma delta (γδ) T cells reside within human tissues including tumors, but their function in mediating antitumor responses to immune checkpoint inhibition is unknown. Here we show that kidney cancers are infiltrated by Vδ2- γδ T cells, with equivalent representation of Vδ1+ and Vδ1- cells, that are distinct from γδ T cells found in normal human tissues. These tumor-resident Vδ2- T cells can express the transcriptional program of exhausted αβ CD8+ T cells as well as canonical markers of terminal T-cell exhaustion including PD-1, TIGIT and TIM-3. Although Vδ2- γδ T cells have reduced IL-2 production, they retain expression of cytolytic effector molecules and co-stimulatory receptors such as 4-1BB. Exhausted Vδ2- γδ T cells are composed of three distinct populations that lack TCF7, are clonally expanded and express cytotoxic molecules and multiple Vδ2- T-cell receptors. Human tumor-derived Vδ2- γδ T cells maintain cytotoxic function and pro-inflammatory cytokine secretion in vitro. The transcriptional program of Vδ2- T cells in pretreatment tumor biopsies was used to predict subsequent clinical responses to PD-1 blockade in patients with cancer. Thus, Vδ2- γδ T cells within the tumor microenvironment can contribute to antitumor efficacy.
Insights
Gamma delta (γδ) T cells in kidney cancer exhibit exhaustion markers but retain anti-tumor functions. Their specific transcriptional profiles can predict patient response to immune checkpoint inhibitors like PD-1 blockade.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Gamma delta (γδ) T cells are tissue-resident immune cells, but their role in anti-tumor immunity, particularly during immune checkpoint inhibition, remains unclear.
- Kidney cancers harbor distinct populations of γδ T cells compared to normal tissues.
Purpose of the Study:
- To investigate the function and characteristics of γδ T cells within the tumor microenvironment.
- To determine if γδ T cells contribute to anti-tumor responses and predict clinical outcomes in patients treated with immune checkpoint inhibitors.
Main Methods:
- Analysis of γδ T cell populations in kidney cancer tissues and normal tissues.
- Transcriptional profiling and characterization of tumor-resident γδ T cells, including markers of exhaustion and effector function.
- In vitro functional assays to assess cytotoxicity and cytokine secretion.
- Correlation of γδ T cell transcriptional programs with clinical response to PD-1 blockade.
Main Results:
- Kidney cancers are infiltrated by Vδ2- γδ T cells distinct from those in normal tissues.
- These tumor-resident γδ T cells display features of T-cell exhaustion (e.g., PD-1, TIGIT, TIM-3) but retain cytotoxic potential and express co-stimulatory receptors (e.g., 4-1BB).
- Transcriptional signatures of Vδ2- γδ T cells in pre-treatment biopsies predicted patient response to PD-1 blockade therapy.
Conclusions:
- Vδ2- γδ T cells within the tumor microenvironment possess anti-tumor cytotoxic functions despite expressing exhaustion markers.
- The transcriptional state of these γδ T cells can serve as a predictive biomarker for clinical response to immune checkpoint inhibition in cancer patients.
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