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 for this work

Research output: Contribution to journal › Journal article › Research › peer-review

13 Citations (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.

Original language	English
Article number	eadl4492
Journal	Science (New York, N.Y.)
Volume	386
Issue number	6718
Number of pages	15
ISSN	0036-8075
DOIs	https://doi.org/10.1126/science.adl4492
Publication status	Published - 2024

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10.1126/science.adl4492

Cite this

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), Article 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.), vol. 386, no. 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.}",

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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

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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.

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DO - 10.1126/science.adl4492

M3 - Journal article

C2 - 39388542

AN - SCOPUS:85206046386

SN - 0036-8075

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

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

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