The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index.
A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade
Open accessAbstract
Immune checkpoint inhibitors (ICIs) produce durable responses in some melanoma patients, but many patients derive no clinical benefit, and the molecular underpinnings of such resistance remain elusive. Here, we leveraged single-cell RNA sequencing (scRNA-seq) from 33 melanoma tumors and computational analyses to interrogate malignant cell states that promote immune evasion. We identified a resistance program expressed by malignant cells that is associated with T cell exclusion and immune evasion. The program is expressed prior to immunotherapy, characterizes cold niches in situ, and predicts clinical responses to anti-PD-1 therapy in an independent cohort of 112 melanoma patients. CDK4/6-inhibition represses this program in individual malignant cells, induces senescence, and reduces melanoma tumor outgrowth in mouse models in vivo when given in combination with immunotherapy. Our study provides a high-resolution landscape of ICI-resistant cell states, identifies clinically predictive signatures, and suggests new therapeutic strategies to overcome immunotherapy resistance.
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“Clinically relevant mechanisms of include mutations in beta-2-microglobulin (B2M) resulting in loss of MHC Class I presentation, downregulation of the antigen presentation machinery, and mutations in the IFNγ-JAK/STAT pathway that impair response to T cell mediated anti-tumor activity7–9.”
From Multimodal pooled Perturb-CITE-seq screens in patient models define mechanisms of cancer immune evasion (2021) · cites this paper as [9]
In the citing paper
“perturbations of B2M, HLA-A, JAK1, JAK2, STAT1, IFNGR1 and IFNGR2 (Fig. 2d,e, Extended Data Fig. 3e,f, Supplementary Table 2) conferred immune evasion, consistent with clinical mechanisms of resistance to immunotherapy7–9.”
From Multimodal pooled Perturb-CITE-seq screens in patient models define mechanisms of cancer immune evasion (2021) · cites this paper as [9]
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“We previously identified an ICR signature, which is predictive of intrinsic resistance to ICI, in a subset of malignant cells in patients with metastatic melanoma using scRNA-seq9.”
From Multimodal pooled Perturb-CITE-seq screens in patient models define mechanisms of cancer immune evasion (2021) · cites this paper as [9]
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“consistent with our previously reported patient and pre-clinical data, where we demonstrate that upregulation of MYC and CDK4/6 (and their transcriptional targets) was associated with increased resistance to immunotherapy, and CDK4/6 inhibitors reduced resistance in human and pre-clinical melanoma models9.”
From Multimodal pooled Perturb-CITE-seq screens in patient models define mechanisms of cancer immune evasion (2021) · cites this paper as [9]
In the citing paper
“This occurs either upon the derepression of endogenous retroviruses and consequent nucleic acid sensing (Goel et al., 2017; Vanpouille-Box et al., 2019) or following the establishment of a permanent cell cycle blockage (i.e., cellular senescence) characterized by an abundant secretory component, the so-called senescence-associated secretory phenotype (SASP) (Jerby-Arnon et al., 2018).”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Jerby-Arnon et al., 2018
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Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review
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Integrating single-cell transcriptomic data across different conditions, technologies, and species
Butler, A., Hoffman, P., Smibert, P., Papalexi, E., & Satija, R. (2018) · Nature Biotechnology · doi:10.1038/nbt.4096 · Cited by 13,174
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Zhang, Y., & Zhang, Z. (2020) · Cellular and Molecular Immunology · doi:10.1038/s41423-020-0488-6 · Cited by 2,906
Tertiary lymphoid structures improve immunotherapy and survival in melanoma
Cabrita, R., Lauss, M., Sanna, A., Donia, M., Skaarup Larsen, M., Mitra, S., Johansson, I., Phung, B., Harbst, K., Vallon-Christersson, J., et al. (2020) · Nature · doi:10.1038/s41586-019-1914-8 · Cited by 2,374
Self-citationThe evolving landscape of biomarkers for checkpoint inhibitor immunotherapy
Havel, J. J., Chowell, D., & Chan, T. A. (2019) · Nature Reviews Cancer · doi:10.1038/s41568-019-0116-x · Cited by 2,286
Single-Cell Analyses Inform Mechanisms of Myeloid-Targeted Therapies in Colon Cancer
Zhang, L., Li, Z., Skrzypczynska, K. M., Fang, Q., Zhang, W., O’Brien, S. A., He, Y., Wang, L., Zhang, Q., Kim, A., et al. (2020) · Cell · doi:10.1016/j.cell.2020.03.048 · Cited by 1,620
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Metadata
- Authors
- Jerby-Arnon, L., Shah, P., Cuoco, M. S., Rodman, C., Su, M.-J., Melms, J. C., Leeson, R., Kanodia, A., Mei, S., Lin, J.-R., Wang, S., Rabasha, B., Liu, D., Zhang, G., Margolais, C., Ashenberg, O., Ott, P. A., Buchbinder, E. I., Haq, R., Hodi, F. S., Boland, G. M., Sullivan, R. J., Frederick, D. T., Miao, B., Moll, T., Flaherty, K. T., Herlyn, M., Jenkins, R. W., Thummalapalli, R., Kowalczyk, M. S., Cañadas, I., Schilling, B., Cartwright, A. N. R., Luoma, A. M., Malu, S., Hwu, P., Bernatchez, C., Forget, M.-A., Barbie, D. A., Shalek, A. K., Tirosh, I., Sorger, P. K., Wucherpfennig, K., Van Allen, E. M., Schadendorf, D., Johnson, B. E., Rotem, A., Rozenblatt-Rosen, O., Garraway, L. A., Yoon, C. H., Izar, B., & Regev, A.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Broad Institute (US)
- Harvard University (US)
- The Wistar Institute (US)
- Massachusetts General Hospital (US)
- Essen University Hospital (DE)
- The University of Texas MD Anderson Cancer Center (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Izar, Benjamin
- ORCID
- Shah, Parin
- Cuoco, Michael S.
- Rodman, Christopher
- Melms, Johannes C.
- Kanodia, Abhay
- Mei, Shaolin
- Lin, Jia-Ren
- Wang, Shu
- Liu, David
- Zhang, Gao
- Ashenberg, Orr
- Ott, Patrick A.
- Buchbinder, Elizabeth I.
- Haq, Rizwan
- Hodi, F. Stephen
- Boland, Genevieve M.
- Sullivan, Ryan J.
- Frederick, Dennie T.
- Moll, Tabea
- Flaherty, Keith T.
- Herlyn, Meenhard
- Jenkins, Russell W.
- Thummalapalli, Rohit
- Kowalczyk, Monika S.
- Cañadas, Israel
- Schilling, Bastian
- Cartwright, Adam N.R.
- Luoma, Adrienne M.
- Hwu, Patrick
- Bernatchez, Chantale
- Forget, Marie-Andrée
- Barbie, David A.
- Shalek, Alex K.
- Tirosh, Itay
- Sorger, Peter K.
- Wucherpfennig, Kai
- Schadendorf, Dirk
- Johnson, Bruce E.
- Rotem, Asaf
- Garraway, Levi A.
- Yoon, Charles H.
- Izar, Benjamin
- Regev, Aviv
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-11
- Volume
- 175
- Issue
- 4
- Pages
- 984-997.e24
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6410377
- OpenAlex
- W2898830231
- Cited by
- 1,429
- References
- 47
- Citations by year
- 2026: 166 · 2025: 187 · 2024: 195 · 2023: 207 · 2022: 203 · 2021: 202 · 2020: 161 · 2019: 102 · 2018: 3
- FWCI
- 44.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- CRI
- NCI (K08-CA222663, 1U24CA180922, R33-CA202820)
- DFCI
- SITC
- Klarman Cell Observatory
- STARR Cancer Consortium
- Koch Institute (P30-CA14051)
- Harvard
- MIT
- AMRF
- Broad Institute
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- melanoma, immune checkpoint inhibitors, immunotherapy resistance, T-cell exclusion, immune evasion, cold tumors, anti-PD-1 therapy, CDK4/6 inhibition, cellular senescence, cancer cell states, predictive biomarkers, combination therapy
- MeSH terms
- Aged, Aged, 80 and over, Animals, Antineoplastic Agents, Female, Humans, Immunotherapy, Male, Melanoma, Mice, Inbred C57BL, Middle Aged, T-Lymphocytes, Tumor Escape, Cell Line, Tumor, Protein Kinase Inhibitors, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Mice, Programmed Cell Death 1 Receptor
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