Epigenetic regulators of clonal hematopoiesis control CD8 T cell stemness during immunotherapy

Tae Gun Kang; Xin Lan; Tian Mi; Hongfeng Chen; Shanta Alli; Song Eun Lim; Sheetal Bhatara; Anoop Babu Vasandan; Grace Ward; Sofia Bentivegna; Josh Jang; Marianne L. Spatz; Jin Hwan Han; Balthasar Clemens Schlotmann; Jakob Schmidt Jespersen; Christopher Derenzo; Peter Vogel; Jiyang Yu; Stephen Baylin; Peter Jones; Casey O'Connell; Kirsten Grønbæk; Ben Youngblood; Caitlin C. Zebley

doi:10.1126/science.adl4492

Epigenetic regulators of clonal hematopoiesis control CD8 T cell stemness during immunotherapy

Tae Gun Kang, Xin Lan, Tian Mi, Hongfeng Chen, Shanta Alli, Song Eun Lim, Sheetal Bhatara, Anoop Babu Vasandan, Grace Ward, Sofia Bentivegna, Josh Jang, Marianne L. Spatz, Jin Hwan Han, Balthasar Clemens Schlotmann, Jakob Schmidt Jespersen, Christopher Derenzo, Peter Vogel, Jiyang Yu, Stephen Baylin, Peter JonesCasey O'Connell, Kirsten Grønbæk, Ben Youngblood^*, Caitlin C. Zebley^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

37 Citationer (Scopus)

Abstract

Epigenetic reinforcement of T cell exhaustion is known to be a major barrier limiting T cell responses during immunotherapy. However, the core epigenetic regulators restricting antitumor immunity during prolonged antigen exposure are not clear. We investigated three commonly mutated epigenetic regulators that promote clonal hematopoiesis to determine whether they affect T cell stemness and response to checkpoint blockade immunotherapy. CD8 T cells lacking Dnmt3a, Tet2, or Asxl1 preserved a progenitor-exhausted (Tpex) population for more than 1 year during chronic antigen exposure without undergoing malignant transformation. Asxl1 controlled the self-renewal capacity of T cells and reduced CD8 T cell differentiation through H2AK119 ubiquitination and epigenetic modification of the polycomb group-repressive deubiquitinase pathway. Asxl1-deficient T cells synergized with anti-PD-L1 immunotherapy to improve tumor control in experimental models and conferred a survival advantage to mutated T cells from treated patients.

Originalsprog	Engelsk
Artikelnummer	eadl4492
Tidsskrift	Science (New York, N.Y.)
Vol/bind	386
Udgave nummer	6718
Antal sider	15
ISSN	0036-8075
DOI	https://doi.org/10.1126/science.adl4492
Status	Udgivet - 2024

Adgang til dokumentet

10.1126/science.adl4492

Citationsformater

Kang, T. G., Lan, X., Mi, T., Chen, H., Alli, S., Lim, S. E., Bhatara, S., Vasandan, A. B., Ward, G., Bentivegna, S., Jang, J., Spatz, M. L., Han, J. H., Schlotmann, B. C., Jespersen, J. S., Derenzo, C., Vogel, P., Yu, J., Baylin, S., ... Zebley, C. C. (2024). Epigenetic regulators of clonal hematopoiesis control CD8 T cell stemness during immunotherapy. Science (New York, N.Y.), 386(6718), Artikel eadl4492. https://doi.org/10.1126/science.adl4492

Kang, TG, Lan, X, Mi, T, Chen, H, Alli, S, Lim, SE, Bhatara, S, Vasandan, AB, Ward, G, Bentivegna, S, Jang, J, Spatz, ML, Han, JH, Schlotmann, BC , Jespersen, JS, Derenzo, C, Vogel, P, Yu, J, Baylin, S, Jones, P, O'Connell, C, Grønbæk, K, Youngblood, B & Zebley, CC 2024, 'Epigenetic regulators of clonal hematopoiesis control CD8 T cell stemness during immunotherapy', Science (New York, N.Y.), bind 386, nr. 6718, eadl4492. https://doi.org/10.1126/science.adl4492

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title = "Epigenetic regulators of clonal hematopoiesis control CD8 T cell stemness during immunotherapy",

abstract = "Epigenetic reinforcement of T cell exhaustion is known to be a major barrier limiting T cell responses during immunotherapy. However, the core epigenetic regulators restricting antitumor immunity during prolonged antigen exposure are not clear. We investigated three commonly mutated epigenetic regulators that promote clonal hematopoiesis to determine whether they affect T cell stemness and response to checkpoint blockade immunotherapy. CD8 T cells lacking Dnmt3a, Tet2, or Asxl1 preserved a progenitor-exhausted (Tpex) population for more than 1 year during chronic antigen exposure without undergoing malignant transformation. Asxl1 controlled the self-renewal capacity of T cells and reduced CD8 T cell differentiation through H2AK119 ubiquitination and epigenetic modification of the polycomb group-repressive deubiquitinase pathway. Asxl1-deficient T cells synergized with anti-PD-L1 immunotherapy to improve tumor control in experimental models and conferred a survival advantage to mutated T cells from treated patients.",

author = "Kang, {Tae Gun} and Xin Lan and Tian Mi and Hongfeng Chen and Shanta Alli and Lim, {Song Eun} and Sheetal Bhatara and Vasandan, {Anoop Babu} and Grace Ward and Sofia Bentivegna and Josh Jang and Spatz, {Marianne L.} and Han, {Jin Hwan} and Schlotmann, {Balthasar Clemens} and Jespersen, {Jakob Schmidt} and Christopher Derenzo and Peter Vogel and Jiyang Yu and Stephen Baylin and Peter Jones and Casey O'Connell and Kirsten Gr{\o}nb{\ae}k and Ben Youngblood and Zebley, {Caitlin C.}",

year = "2024",

doi = "10.1126/science.adl4492",

language = "English",

volume = "386",

journal = "Science (New York, N.Y.)",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

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T1 - Epigenetic regulators of clonal hematopoiesis control CD8 T cell stemness during immunotherapy

AU - Kang, Tae Gun

AU - Lan, Xin

AU - Mi, Tian

AU - Chen, Hongfeng

AU - Alli, Shanta

AU - Lim, Song Eun

AU - Bhatara, Sheetal

AU - Vasandan, Anoop Babu

AU - Ward, Grace

AU - Bentivegna, Sofia

AU - Jang, Josh

AU - Spatz, Marianne L.

AU - Han, Jin Hwan

AU - Schlotmann, Balthasar Clemens

AU - Jespersen, Jakob Schmidt

AU - Derenzo, Christopher

AU - Vogel, Peter

AU - Yu, Jiyang

AU - Baylin, Stephen

AU - Jones, Peter

AU - O'Connell, Casey

AU - Grønbæk, Kirsten

AU - Youngblood, Ben

AU - Zebley, Caitlin C.

PY - 2024

Y1 - 2024

N2 - Epigenetic reinforcement of T cell exhaustion is known to be a major barrier limiting T cell responses during immunotherapy. However, the core epigenetic regulators restricting antitumor immunity during prolonged antigen exposure are not clear. We investigated three commonly mutated epigenetic regulators that promote clonal hematopoiesis to determine whether they affect T cell stemness and response to checkpoint blockade immunotherapy. CD8 T cells lacking Dnmt3a, Tet2, or Asxl1 preserved a progenitor-exhausted (Tpex) population for more than 1 year during chronic antigen exposure without undergoing malignant transformation. Asxl1 controlled the self-renewal capacity of T cells and reduced CD8 T cell differentiation through H2AK119 ubiquitination and epigenetic modification of the polycomb group-repressive deubiquitinase pathway. Asxl1-deficient T cells synergized with anti-PD-L1 immunotherapy to improve tumor control in experimental models and conferred a survival advantage to mutated T cells from treated patients.

AB - Epigenetic reinforcement of T cell exhaustion is known to be a major barrier limiting T cell responses during immunotherapy. However, the core epigenetic regulators restricting antitumor immunity during prolonged antigen exposure are not clear. We investigated three commonly mutated epigenetic regulators that promote clonal hematopoiesis to determine whether they affect T cell stemness and response to checkpoint blockade immunotherapy. CD8 T cells lacking Dnmt3a, Tet2, or Asxl1 preserved a progenitor-exhausted (Tpex) population for more than 1 year during chronic antigen exposure without undergoing malignant transformation. Asxl1 controlled the self-renewal capacity of T cells and reduced CD8 T cell differentiation through H2AK119 ubiquitination and epigenetic modification of the polycomb group-repressive deubiquitinase pathway. Asxl1-deficient T cells synergized with anti-PD-L1 immunotherapy to improve tumor control in experimental models and conferred a survival advantage to mutated T cells from treated patients.

U2 - 10.1126/science.adl4492

DO - 10.1126/science.adl4492

M3 - Journal article

C2 - 39388542

AN - SCOPUS:85206046386

SN - 0036-8075

VL - 386

JO - Science (New York, N.Y.)

JF - Science (New York, N.Y.)

IS - 6718

M1 - eadl4492

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