PD-1-induced T cell exhaustion is controlled by a Drp1-dependent mechanism

Simula, Luca; Cancila, Valeria; Antonucci, Ylenia; Colamatteo, Alessandra; Procaccini, Claudio; Matarese, Giuseppe; Tripodo, Claudio; Campello, Silvia

doi:10.1101/2020.07.14.200592

Cited by 4 publications

(5 citation statements)

References 45 publications

(129 reference statements)

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“…Since PD-1 signals dynamically influence mitochondrial functions resulting in compromised function of effector T cells along with large tumor burdens [17][18][19][20][21][22] , we measured the mitochondrial membrane potential (DYm) of CX3CR1 + CD8 + T cells to determine the functional state of their mitochondria, as a start to understanding T cell resilience. According to the level of DYm, we found CX3CR1 + CD8 + T cells with low DYm to be more responsive to radiation therapy in patients with large tumor burdens.…”

Section: Discussionmentioning

confidence: 99%

“…We hypothesized that a change in the functional state of CX3CR1 + CD8 + T cells may reflect an optimal response to a successful SFRT. Given the presence of large tumor burden in these patients in which compromised mitochondrial function has been linked to T cell exhaustion [17][18][19][20][21][22] , we measured the CTL function of CX3CR1 + CD8 + T cells along with their mitochondrial membrane potential (DYm) to determine their mitochondrial function. The CTL function of these T cells was measured by CD107a expression, which reflects degranulation and cytotoxicity.…”

Section: Cx3cr1 and Low Mitochondria Membrane Potential Identify Resi...mentioning

confidence: 99%

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Resilient CD8⁺T cells maintain a high cytotoxic capacity by balancing ROS via ME1 upregulation

Gicobi

Mao

DeFranco

et al. 2022

Preprint

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Cytotoxic T lymphocytes (CTL) are indispensable in anti-tumor immunity. Although CTLs are prone to exhaustion in patients with advanced cancer, T cell resiliency explains the presence of tumor-reactive CTLs that are less exhausted, capable of cytolytic function, expand, and rebound in response to immunotherapy to reject metastatic malignancies. However, the features of resilient T cells have not been clearly defined. In this report, we demonstrate peripheral CX3CR1+ CD8+ T cells with low mitochondrial membrane potential portray a functional resiliency in patients with large tumor burden as their CTL function rebounded quickly after radiation therapy. Furthermore, CX3CR1+ CD8+ T cell with low, but not high, mitochondrial membrane potential are highly cytotoxic, accumulate less reactive oxygen species (ROS) and express more Malic enzyme 1 (ME1). ME1 overexpression increases ATP production in a glycolysis-independent manner while concurrently curtailing excessive ROS in activated CD8+ T cells; and expands CX3CR1+NKG7+ effector CD8+ T cells with enhanced cytotoxicity. Importantly, transfection of ME1 mRNA promotes tumoricidal activity in CD8+ T cells from patients with advanced cancers. Our study reveals a mechanism used by CTLs to balance excessive ROS via ME1 to maintain a metabolic and functional resiliency. Modification of ME1 expression in CTLs may be a novel method to improve the efficacy of cancer immunotherapy by preventing T cell exhaustion.

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Section: Discussionmentioning

confidence: 99%

Section: Cx3cr1 and Low Mitochondria Membrane Potential Identify Resi...mentioning

confidence: 99%

Resilient CD8⁺T cells maintain a high cytotoxic capacity by balancing ROS via ME1 upregulation

Gicobi

Mao

DeFranco

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…Western blots were performed as previously described 78 . The following primary anti-human antibodies have been used: anti-actin (Cell Signaling 4970), anti-OGDH (Sigma Aldrich HPA019514), anti-Hsp90 (Cell Signaling 4877S), anti-PDHA1+A2 (Cell Signaling 2784S) and OxPhos Human WB Antibody Cocktail (Thermo Fisher 45-8199).…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial metabolism sustains CD8⁺T cell migration for an efficient infiltration into solid tumors

Simula,

Fumagalli,

Vimeux

et al. 2024

Preprint

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The ability of CD8+ T cells to infiltrate solid tumors and reach cancer cells is associated with improved patient survival and responses to immunotherapy. Thus, identifying the factors controlling T cell migration in tumors is critical, so that strategies to intervene on these targets can be developed. Although interstitial motility is a highly energy-demanding process, the metabolic requirements of CD8+ T cells migrating in a 3D environment remain unclear. Here, we demonstrate that the tricarboxylic acid (TCA) cycle is the main metabolic pathway sustaining human CD8+ T cell motility in 3D collagen gels and tumor slices while glycolysis plays a much minor role. Using pharmacological and genetic approaches, we report that CD8+ T cell migration depends on the mitochondrial oxidation of glucose and glutamine, but not fatty acids, and both ATP and ROS produced by mitochondria are required for T cells to migrate. Pharmacological interventions to increase mitochondrial activity improve CD8+ T cells intra-tumoral migration and CAR T cell recruitment into tumor islets leading to better control of tumor growth in human xenograft models. Our study highlights the rationale of targeting mitochondrial metabolism to enhance the migration and antitumor efficacy of CAR T cells in treating solid tumors.

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“…Western blots were performed as previously described in ref. 79. Briefly, cells have been lysed in RIPA buffer 20 min on ice (Tris-HCl 50 mM pH8, NaCl 150 mM, Nonidet-P40 1%, Sodium deoxycolate 0.5%, SDS 0.1%) supplemented with Protease Inhibitor Cocktail (Thermo Fisher 78429) and 1 mM NaVO 4 .…”

Section: Western Blotmentioning

confidence: 99%

Mitochondrial metabolism sustains CD8+ T cell migration for an efficient infiltration into solid tumors

Simula,

Fumagalli,

Vimeux

et al. 2024

Nat Commun

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The ability of CD8+ T cells to infiltrate solid tumors and reach cancer cells is associated with improved patient survival and responses to immunotherapy. Thus, identifying the factors controlling T cell migration in tumors is critical, so that strategies to intervene on these targets can be developed. Although interstitial motility is a highly energy-demanding process, the metabolic requirements of CD8+ T cells migrating in a 3D environment remain unclear. Here, we demonstrate that the tricarboxylic acid (TCA) cycle is the main metabolic pathway sustaining human CD8+ T cell motility in 3D collagen gels and tumor slices while glycolysis plays a more minor role. Using pharmacological and genetic approaches, we report that CD8+ T cell migration depends on the mitochondrial oxidation of glucose and glutamine, but not fatty acids, and both ATP and ROS produced by mitochondria are required for T cells to migrate. Pharmacological interventions to increase mitochondrial activity improve CD8+ T cell intratumoral migration and CAR T cell recruitment into tumor islets leading to better control of tumor growth in human xenograft models. Our study highlights the rationale of targeting mitochondrial metabolism to enhance the migration and antitumor efficacy of CAR T cells in treating solid tumors.

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PD-1-induced T cell exhaustion is controlled by a Drp1-dependent mechanism

Cited by 4 publications

References 45 publications

Resilient CD8⁺T cells maintain a high cytotoxic capacity by balancing ROS via ME1 upregulation

Resilient CD8⁺T cells maintain a high cytotoxic capacity by balancing ROS via ME1 upregulation

Mitochondrial metabolism sustains CD8⁺T cell migration for an efficient infiltration into solid tumors

Mitochondrial metabolism sustains CD8+ T cell migration for an efficient infiltration into solid tumors

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PD-1-induced T cell exhaustion is controlled by a Drp1-dependent mechanism

Cited by 4 publications

References 45 publications

Resilient CD8+T cells maintain a high cytotoxic capacity by balancing ROS via ME1 upregulation

Resilient CD8+T cells maintain a high cytotoxic capacity by balancing ROS via ME1 upregulation

Mitochondrial metabolism sustains CD8+T cell migration for an efficient infiltration into solid tumors

Mitochondrial metabolism sustains CD8+ T cell migration for an efficient infiltration into solid tumors

Contact Info

Product

Resources

About

Resilient CD8⁺T cells maintain a high cytotoxic capacity by balancing ROS via ME1 upregulation

Resilient CD8⁺T cells maintain a high cytotoxic capacity by balancing ROS via ME1 upregulation

Mitochondrial metabolism sustains CD8⁺T cell migration for an efficient infiltration into solid tumors