Salvage therapy expands highly cytotoxic and metabolically fit resilient CD8+ T cells via ME1 upregulation

Sep 24, 2026

Advanced cancer patients who do not respond to or progress on immune checkpoint inhibitors may receive salvage radiotherapy to lessen tumor burden and symptoms. Some show marked global regression accompanied by a rebound of cytotoxic CD8+ T cells, termed T cell resilience. Resilient cells are enriched for CX3CR1+ CD8+ T cells with low mitochondrial membrane potential, reduced reactive oxygen species, and increased malic enzyme 1 (ME1). ME1 overexpression boosts effector CD8+ cytotoxicity, expansion, and mitochondrial respiration while maintaining redox balance via type I interferon signaling.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages18

Reading Time45 min

AccessFree to download

Introduction

Rescue response after immune checkpoint inhibitors

Defining T cell resilience

Identifying resilient CD8+ T cell markers

Role of CX3CR1 and TMRM (mitochondrial membrane potential)

Mechanistic findings

ME1 links low MMP, reduced ROS, and cytotoxic expansion

Type I interferon pathway and redox balance

IMMUNOLOGY Salvage therapy expands highly cytotoxic and metabolically fit resilient CD8+ T cells via ME1 upregulation Joanina K. Gicobi1, Zhiming Mao1, Grace DeFranco1, Jacob B. Hirdler2, Ying Li3, Vianca V. Vianzon1, Emilia R. Dellacecca1, Michelle A. Hsu1, Whitney Barham1, Yiyi Yan4, Aaron S. Mansfield5, Yi Lin5, Xiaosheng Wu5, Taro Hitosugi6, Dawn Owen7, Michael P. Grams7, Jacob J. Orme5, Fabrice Lucien2, Hu Zeng1,8, Sean S. Park7, Haidong Dong1,2* Patients with advanced cancers who either do not experience initial response to or progress while on immune checkpoint inhibitors (ICIs) receive salvage radiotherapy to reduce tumor burden and tumor-related symptoms. Occasionally, some patients experience substantial global tumor regression with a rebound of cytotoxic CD8+ T cells. We have termed the rebound of cytotoxic CD8+ T cells in response to salvage therapy as T cell resilience and examined the underlying mechanisms of resilience. Resilient T cells are enriched for CX3CR1+ CD8+ T cells with low mitochondrial membrane potential, accumulate less reactive oxygen species (ROS), and express more malic enzyme 1 (ME1). ME1 overexpression enhanced the cytotoxicity and expansion of effector CD8+ T cells partially via the type I interferon pathway. ME1 also increased mitochondrial respiration while maintaining the redox state balance. ME1 increased the cytotoxicity of peripheral lymphocytes from patients with advanced cancers. Thus, preserved resilient T cells in patients rebound after salvage therapy and ME1 enhances their resiliency. Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC) . INTRODUCTION Patients with advanced cancers that are refractory to current therapies are treated with salvage radiotherapy or chemotherapy with or without a combination with immune checkpoint inhibitors (ICIs)( 1, 2) . Occasionally, some of these patients experience substantial tumor regression following salvage therapy in combination with ICI therapy (3, 4) . It has been reported that a successful ICI therapy expands tumor-reactive CD8+ T cells with effector phenotype in peripheral blood, which have the potential to replace exhausted CD8+ T cells inside tumor tissue (5–9) . We and others have identified tumoricidal CX3CR1+ CD8+ T cells that are responsive to ICI therapy in both preclinical and clinical settings (8, 10, 11). CX3CR1+ CD8+ T cells also increased in patients with metastatic diseases who do not respond to initial ICI therapy but respond to subsequent combination therapy (chemotherapy plus ICI) (8) . Since CX3CR1+ CD8+ T cells are highly cytotoxic and effective in preclinical models and in the peripheral blood of patients who respond to ICI therapy (7, 8, 10), we proposed the term “T cell resilience” to explain such clinical observations, where effective cytotoxic T cells rebound in response to appropriate combination therapy (3, 4) and can reduce systemic tumor burden. Accordingly, a computational model of T cell resilience has been established in the prediction of patient response to ICI therapy (12) . However, the underlying mechanisms of T cell resilience are yet to be defined. 1Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA. 2Department of Urology, Mayo Clinic, Rochester, MN, USA. 3Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, USA. 4Division of Medical Oncology, Mayo Clinic, Jacksonville, FL, USA. 5Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA. 6Department of Oncology, Mayo Clinic, Rochester, MN, USA. 7Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA. 8Department of Rheumatology, Mayo Clinic, Rochester, MN, USA. *Corresponding author. Email: [dong.haidong@mayo.edu](dong.haidong@mayo.edu)[ ](dong.haidong@mayo.ed

FAQs

What is T cell resilience in the context of salvage therapy?

T cell resilience refers to the rebound of cytotoxic CD8+ T cells observed after salvage therapy, especially in some patients who then experience substantial tumor regression.

Which cellular traits characterize resilient CD8+ T cells?

Resilient CD8+ T cells are enriched for CX3CR1+ cells with low mitochondrial membrane potential, accumulate less reactive oxygen species, and express higher malic enzyme 1 (ME1).

How does ME1 influence resilient CD8+ T cell function?

ME1 overexpression enhances cytotoxicity and expansion of effector CD8+ T cells, partially through the type I interferon pathway, while increasing mitochondrial respiration and maintaining redox state balance.

Sep 24, 2026

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