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Peer-reviewedCC BY-NC-NDCancer immunology research

Cullin-5 RING E3 ligase limits CD8+ T-cell persistence and effector responses during chronic antigen stimulation

  • Justin D. Saco1,2
  • Daniel Karin1,2
  • J.J. Patten1,2
  • Stefanie Bachl3
  • Carter Ching3
  • Nupura Kale3
  • Yichen Fan2
  • Egmidio Medina1,2
  • Nataly Naser Al Deen2
  • Ameya Champhekar2,4
  • William G. Kaelin5
  • Brenda A. Schulman6
4 more authors
  • Katie M. Campbell2,4,7
  • Julia Carnevale7,8,9,10
  • Cristina Puig-Saus4,7,11,12
  • Antoni Ribas1,2,4,7,12
12 affiliations
  1. 1Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA
  2. 2Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles, Los Angeles, CA, USA
  3. 3Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA
  4. 4Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA
  5. 5Dana Farber Cancer Institute, Harvard University, Cambridge, MA, USA
  6. 6Department Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany
  7. 7Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA
  8. 8Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
  9. 9UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
  10. 10Weill Cancer Hub West, Stanford University and University of California, San Francisco, CA, USA
  11. 11Department of Microbiology, Immunology and Medical Genetics, University of California Los Angeles, Los Angeles, CA, USA
  12. 12Department of Surgery, Division of Surgical Oncology, University of California Los Angeles, Los Angeles, CA, USA
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Abstract

T-cell exhaustion limits durable antitumor responses and remains a barrier to adoptive cell therapies (ACT) in solid tumors. To identify regulators of T-cell persistence, we performed genome-wide CRISPR knockout screens in primary human CD8+ T cells expressing an NY-ESO-1–specific T-cell receptor and subjected them to repeat tumor cell rechallenges. These screens revealed an enrichment of single-guide RNAs targeting components of cullin–RING E3 ubiquitin ligases, particularly cullin-5–RING E3 ligase (CRL5) assemblies comprising CUL5, RNF7, and ARIH2. Disruption of CRL5 genes in T cells preserved cytotoxic activity and enhanced cytokine production while sustaining effector-associated transcriptional programs and suppressing exhaustion-related signatures. Pharmacologic inhibition of cullin neddylation with the NEDD8-activating enzyme inhibitor MLN4924 recapitulated CRL5 loss and enhanced T-cell effector function in vitro. In a human melanoma xenograft model, ACT with CRL5-deficient T cells improved tumor control. Together, these findings identify CRL5 as a negative regulator of T-cell fitness and a potential therapeutic target to enhance ACT durability in solid tumors. Significance: The CRL5 complex negatively regulates CD8+ T-cell persistence during chronic antigen stimulation, identifying CRL5 disruption as a potential strategy to sustain T-cell effector function and improve ACT. See related commentary by Hanina and Maus, p. XX . See related article by Bachl et al., p. XX .

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Cite

BibTeXRIS
BibTeX
@article{saco2026cullin5,
  title = {{Cullin-5 RING E3 ligase limits CD8+ T-cell persistence and effector responses during chronic antigen stimulation}},
  author = {Justin D. Saco and Daniel Karin and J.J. Patten and Stefanie Bachl and Carter Ching and Nupura Kale and Yichen Fan and Egmidio Medina and Nataly Naser Al Deen and Ameya Champhekar and William G. Kaelin and Brenda A. Schulman and Katie M. Campbell and Julia Carnevale and Cristina Puig-Saus and Antoni Ribas},
  journal = {Cancer immunology research},
  year = {2026},
  month = oct,
  doi = {10.1158/2326-6066.cir-26-0181},
  url = {https://doi.org/10.1158/2326-6066.cir-26-0181},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Cullin-5 RING E3 ligase limits CD8+ T-cell persistence and effector responses during chronic antigen stimulation
AU  - Justin D. Saco
AU  - Daniel Karin
AU  - J.J. Patten
AU  - Stefanie Bachl
AU  - Carter Ching
AU  - Nupura Kale
AU  - Yichen Fan
AU  - Egmidio Medina
AU  - Nataly Naser Al Deen
AU  - Ameya Champhekar
AU  - William G. Kaelin
AU  - Brenda A. Schulman
AU  - Katie M. Campbell
AU  - Julia Carnevale
AU  - Cristina Puig-Saus
AU  - Antoni Ribas
PY  - 2026
DA  - 2026/10/15
JO  - Cancer immunology research
DO  - 10.1158/2326-6066.cir-26-0181
UR  - https://doi.org/10.1158/2326-6066.cir-26-0181
AB  - T-cell exhaustion limits durable antitumor responses and remains a barrier to adoptive cell therapies (ACT) in solid tumors. To identify regulators of T-cell persistence, we performed genome-wide CRISPR knockout screens in primary human CD8+ T cells expressing an NY-ESO-1–specific T-cell receptor and subjected them to repeat tumor cell rechallenges. These screens revealed an enrichment of single-guide RNAs targeting components of cullin–RING E3 ubiquitin ligases, particularly cullin-5–RING E3 ligase (CRL5) assemblies comprising CUL5, RNF7, and ARIH2. Disruption of CRL5 genes in T cells preserved cytotoxic activity and enhanced cytokine production while sustaining effector-associated transcriptional programs and suppressing exhaustion-related signatures. Pharmacologic inhibition of cullin neddylation with the NEDD8-activating enzyme inhibitor MLN4924 recapitulated CRL5 loss and enhanced T-cell effector function in vitro. In a human melanoma xenograft model, ACT with CRL5-deficient T cells improved tumor control. Together, these findings identify CRL5 as a negative regulator of T-cell fitness and a potential therapeutic target to enhance ACT durability in solid tumors. Significance: The CRL5 complex negatively regulates CD8+ T-cell persistence during chronic antigen stimulation, identifying CRL5 disruption as a potential strategy to sustain T-cell effector function and improve ACT. See related commentary by Hanina and Maus, p. XX . See related article by Bachl et al., p. XX .
SN  - 2326-6066
SN  - 2326-6074
ER  -