The DOI matches its Crossref record; 68 of the 69 references it cites were found in a registry or an index.
Intrinsic Immunogenicity of Small Cell Lung Carcinoma Revealed by Its Cellular Plasticity
Open accessPublished version of a preprint
Abstract
Small cell lung carcinoma (SCLC) is highly mutated, yet durable response to immune checkpoint blockade (ICB) is rare. SCLC also exhibits cellular plasticity, which could influence its immunobiology. Here we discover that a distinct subset of SCLC uniquely upregulates MHC I, enriching for durable ICB benefit. In vitro modeling confirms epigenetic recovery of MHC I in SCLC following loss of neuroendocrine differentiation, which tracks with derepression of STING. Transient EZH2 inhibition expands these nonneuroendocrine cells, which display intrinsic innate immune signaling and basally restored antigen presentation. Consistent with these findings, murine nonneuroendocrine SCLC tumors are rejected in a syngeneic model, with clonal expansion of immunodominant effector CD8 T cells. Therapeutically, EZH2 inhibition followed by STING agonism enhances T-cell recognition and rejection of SCLC in mice. Together, these data identify MHC I as a novel biomarker of SCLC immune responsiveness and suggest novel immunotherapeutic approaches to co-opt SCLC's intrinsic immunogenicity. Significance: SCLC is poorly immunogenic, displaying modest ICB responsiveness with rare durable activity. In profiling its plasticity, we uncover intrinsically immunogenic MHC Ihi subpopulations of nonneuroendocrine SCLC associated with durable ICB benefit. We also find that combined EZH2 inhibition and STING agonism uncovers this cell state, priming cells for immune rejection. This article is highlighted in the In This Issue feature, p. 1861
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“recent studies have provided compelling evidence that tumor cell-intrinsic STING activity is also an important contributor34–36.”
From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [36]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625
clusterProfiler: an R Package for Comparing Biological Themes Among Gene Clusters
Yu, G., Wang, L.-G., Han, Y., & He, Q.-Y. (2012) · OMICS: A Journal of Integrative Biology · doi:10.1089/omi.2011.0118 · Cited by 36,259
Model-based Analysis of ChIP-Seq (MACS)
Zhang, Y., Liu, T., Meyer, C. A., Eeckhoute, J., Johnson, D. S., Bernstein, B. E., Nusbaum, C., Myers, R. M., Brown, M., Li, W., et al. (2008) · Genome Biology · doi:10.1186/gb-2008-9-9-r137 · Cited by 18,386
Differential expression analysis for sequence count data
Anders, S., & Huber, W. (2010) · Genome Biology · doi:10.1186/gb-2010-11-10-r106 · Cited by 15,581
Robinson, J. T., Thorvaldsdóttir, H., Winckler, W., Guttman, M., Lander, E. S., Getz, G., & Mesirov, J. P. (2011) · Nature Biotechnology · doi:10.1038/nbt.1754 · Cited by 15,390
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
Scenic: single-cell regulatory network inference and clustering.
Aibar, S., González-Blas, C. B., Moerman, T., Huynh-Thu, V. A., Imrichova, H., Hulselmans, G., Rambow, F., Marine, J.-C., Geurts, P., Aerts, J., et al. (2017) · Nature Methods · doi:10.1038/nmeth.4463 · Cited by 6,520
Improved vectors and genome-wide libraries for CRISPR screening
Sanjana, N. E., Shalem, O., & Zhang, F. (2014) · Nature Methods · doi:10.1038/nmeth.3047 · Cited by 5,239
Genome-scale CRISPR-Cas9 knockout screening in human cells
Shalem, O., Sanjana, N. E., Hartenian, E., Shi, X., Scott, D. A., Mikkelsen, T. S., Heckl, D., Ebert, B. L., Root, D. E., Doench, J. G., et al. (2014) · Science · doi:10.1126/science.1247005 · Cited by 5,234
Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR-Cas9
Doench, J. G., Fusi, N., Sullender, M., Hegde, M., Vaimberg, E. W., Donovan, K. F., Smith, I., Tothova, Z., Wilen, C., Orchard, R., et al. (2016) · Nature Biotechnology · doi:10.1038/nbt.3437 · Cited by 4,637
Cited by
Sorted by citations
Items 201–232 of 232
Khan, P., Siddiqui, J. A., Ps, K., Venkata, R. C., Maurya, S. K., Mirzapoiazova, T., Perumal, N., Chaudhary, S., Kanchan, R. K., Fatima, M., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22602973
Redín, E., Sridhar, H., Zhan, Y. A., Pereira Mello, B., Zhong, H., Durani, V., Sabet, A. H., Manoj, P., Linkov, I., Qiu, J., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26756173
Parveen, S., Adhinaveni, R., Fang, K., Choppavarapu, L., Du, M., Leone, G. W., Sarkar, N. D., Jin, V. X., & Chen, H.-Z. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.01.26.701784 · Cited by 1
Cell state-specific metabolic networks govern ferroptosis versus apoptosis in small cell lung cancerPreprint
Kim, J. W., Bebber, C. M., Dai, Y., Bopp, S., Edenhofer, A., Li, A. M., Rösner, T. N., Berning, L., Yang, M., Leak, L. B., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.03.27.714827
Fernández, L. T., Boehm, V., Kaufmann, J., Rumińska, A., Becker, J. P., Márquez, M. G., de Bruijn, B., Müller, C., Alavinejad, N., Lovric, L., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.03.31.715503
Epigenetic characterization of cellular pliancy in breast cancer
Benhassoun, R. (2024) · theses.fr (ABES) · doi:10.70675/0b1d39b2za3d7z4b26zb4b0zaafa77d5068a
Liu, L., Wu, Q., Fang, S., Hu, Z., Yu, S., Wang, H., Song, H., & Liu, Q. (2026) · Cancer Letters · doi:10.1016/j.canlet.2026.218516
Gao, Q., Wei, K., Pan, D., Xi, Y., Xu, C., & Jia, D. (2026) · Biomedicines · doi:10.3390/biomedicines14050973
PTPN2 inhibition unleashes response to STING agonism in head and neck squamous cell cancer
Li, Z., Fu, C., Sehgal, K., Egloff, A. M., Thai, T. C., Monge, O. A., Chuong, C. L., Senent, Y., Lineberry, M. S., Eschle, B. K., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-72372-1
Self-citationReframing small cell lung cancer: therapeutic lessons from hematologic malignancies
Parmar, K., Surolia, I., & Thomas, A. (2026) · Frontiers in Oncology · doi:10.3389/fonc.2026.1821271
Peng, P., Sang, L., Yang, X., Meng, Y., & Liang, F. (2026) · Research Square · doi:10.21203/rs.3.rs-9639268/v1
Prognostic impact of baseline blood biomarkers in SCLC first-line treatment
Wang, Y., Ren, M., Liu, J., Xiang, Z., Ding, H., Xie, J., Ding, N., & Yang, Y. (2026) · Therapeutic Advances in Medical Oncology · doi:10.1177/17588359261450062
Trained immunity-primed DLL3-targeted CAR macrophages for the eradication of small cell lung cancer
Ying, H., Wang, Y., Li, N., Ma, W., Shou, X., Liu, Z., Chen, C., Dong, Z., Li, H.-W., Zhang, J., et al. (2026) · Journal of Advanced Research · doi:10.1016/j.jare.2026.05.047
Hao, Z., Villano, J. L., Arnold, S. M., & Anthony, L. B. (2026) · Therapeutic Advances in Medical Oncology · doi:10.1177/17588359261458324
Neurotropism and Therapeutic Targeting of Brain Metastases in Small Cell Lung Cancer
Sen, T., Gobbini, É., Mustafayev, K., Spiegelman, L. S., Akkoc-Mustafayev, F. N., Hirsch, F. R., Alahmadi, A. A., & Ahluwalia, M. S. (2026) · Cancer Research · doi:10.1158/0008-5472.can-25-5968
Research on Thoracic Cancer: Lung Cancer
Calkins, K., Jiang, T., & Huang, J. (2026) · Springer eBooks · doi:10.1007/978-3-032-19175-5_17
Kim, J., & Kang, S. (2026) · Pharmaceuticals · doi:10.3390/ph19081217
Han, Z., Tong, J., Feng, Y., Zhu, K., Han, Y., Xiao, X., Li, Y., & Xia, S. (2026) · Biochemical Pharmacology · doi:10.1016/j.bcp.2026.118322
Biomarker-driven insights into immune checkpoint inhibitor therapy in small-cell lung cancer
Shuxing, W., Zhao, X., Zeng, Y., Li, W., Huang, J., Leung, E. L., Png, S., Liang, A., Li, Y., Guan, Q., et al. (2026) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2026.105517
Li, Y., Laimon, Y. N., Cho, H., Vivero, M., Oliveira, G. R. D., Seager, M. D., Delcea, A., Savla, V., Chen, Y., Durmaz, Y. T., et al. (2025) · Journal of Clinical Investigation · doi:10.1016/j.jtho.2025.07.028 · Cited by 2
Self-citationThe Five-Decade Journey of Small Cell Lung Cancer
Chen, R., Xue, C., Zhong, Y., Huang, Q., Fan, Q., Li, Y., Wu, J., Dong, S., Li, X., Xiao, T., et al. (2026) · 癌症：英文版 · doi:10.34133/cancomm.0052
Fernández, L. T., Boehm, V., Kaufmann, J., Becker, J. P., Márquez, M. G., de Bruijn, B., Rumińska, A., Müller, C., Bosco, G., Alavinejad, N., et al. (2026) · Molecular Cancer · doi:10.1186/s12943-026-02750-2
Xu, H., Li, B., Yang, J., & Tang, X. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1900927
Genomic and Transcriptomic Features of Relapsed SCLC
Devarakonda, S., Hoang, M., Sankararaman, S., Skidmore, Z. L., Herzog, B. H., Pepin, K., McMichael, J. F., Ward, J. P., Morgensztern, D., Waqar, S. N., et al. (2026) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2026.104201
Lü, S., Yu, Y., Zhang, J., Wang, Q., Cho, E. K., Zhao, J., Kim, S. H., Lee, Y., Clay, T. D., Yang, T.-Y., et al. (2026) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2026-015474
Transcriptional networks underlying tumour plasticity in small-cell lung cancerPreprint
Bhattacharya, D., Groves, S. M., Walker, C. R., Duorino, G. N., Hsieh, M., Chtourou, Y., Hartmann, G. G., Hsu, W., Liu, C. C., Angelo, M., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.09.26.754526
Gao, Q., Wei, K., Pan, D., Xu, C., Xi, Y., Zhang, Y., Augert, A., MacPherson, D. P., & Jia, D. (2026) · Science Advances · doi:10.1126/sciadv.aef1693
Targeting MYC in small cell lung cancer: Bridging molecular subtypes and therapeutic vulnerability
Rosa, C. D., Diaz, C. A., Morillas, J. M., Sánchez‐Céspedes, M., & Corte, C. M. D. (2026) · Lung Cancer · doi:10.1016/j.lungcan.2026.109672
Cell-state-specific metabolic networks govern ferroptosis versus apoptosis in small cell lung cancer
Kim, J. W., Bebber, C. M., Dai, Y., Bopp, S., Edenhofer, A., Li, A. M., Rösner, T. N., Berning, L., Yang, M., Leak, L. B., et al. (2026) · Cell · doi:10.1016/j.cell.2026.09.045
Sun, Y., Zhao, X., Zhang, J., Song, Q., Cheng, M., Chen, Y., Liu, Y., Hou, W., Fu, W., Zhang, X., et al. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1999309
Liu, T., Zhou, T., Mo, S., Ge, M., Ma, W., Zhan, J., Chen, X., Yang, Y., Ma, Y., Luo, N., et al. (2026) · MedComm · doi:10.1002/mco2.71118
Metadata
- Authors
- Mahadevan, N. R., Knelson, E. H., Wolff, J. O., Vajdi, A., Saigí, M., Campisi, M., Hong, D., Thai, T. C., Piel, B., Han, S., Reinhold, B. B., Duke-Cohan, J. S., Poitras, M. J., Taus, L. J., Lizotte, P. H., Portell, A., Quadros, V., Santucci, A. D., Murayama, T., Cañadas, I., Kitajima, S., Akitsu, A., Fridrikh, M., Watanabe, H., Reardon, B., Gokhale, P. C., Paweletz, C. P., Awad, M. M., Van Allen, E. M., Lako, A., Wang, X.-T., Chen, B., Hong, F., Sholl, L. M., Tolstorukov, M. Y., Pfaff, K., Jänne, P. A., Gjini, E., Edwards, R., Rodig, S., Reinherz, E. L., Oser, M. G., & Barbie, D. A.
- Affiliations
- Brigham and Women's Hospital (US)
- Dana-Farber Cancer Institute (US)
- Politecnico di Torino (IT)
- Harvard University (US)
- 6Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, Massachusetts.
- Fox Chase Cancer Center (US)
- Tisch Cancer Institute (US)
- 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
- Bristol-Myers Squibb (United States) (US)
- 14Translational Pathology, Bristol Myers Squibb, Trenton, New Jersey.
- Corresponding author
- Oser, Matthew G.
- Barbie, David A.
- ORCID
- Mahadevan, Navin R.
- Knelson, Erik H.
- Wolff, Jacquelyn O.
- Vajdi, Amir
- Saigí, Maria
- Campisi, Marco
- Hong, Deli
- Thai, Tran C.
- Piel, Brandon
- Han, Saemi
- Duke-Cohan, Jonathan S.
- Taus, Luke J.
- Lizotte, Patrick H.
- Portell, Andrew
- Quadros, Victor
- Santucci, Alison D.
- Murayama, Takahiko
- Cañadas, Israel
- Kitajima, Shunsuke
- Akitsu, Aoi
- Watanabe, Hideo
- Reardon, Brendan
- Gokhale, Prafulla C.
- Paweletz, Cloud P.
- Awad, Mark M.
- Lako, Ana
- Hong, Fangxin
- Sholl, Lynette M.
- Tolstorukov, Michael Y.
- Pfaff, Kathleen
- Gjini, Evisa
- Edwards, Robin
- Rodig, Scott
- Reinherz, Ellis L.
- Oser, Matthew G.
- Barbie, David A.
- Venue
- Cancer Discovery
- Published
- 2021-03-11
- Volume
- 11
- Issue
- 8
- Pages
- 1952-1969
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC8338750
- OpenAlex
- W3134054679
- Cited by
- 227
- References
- 69
- Citations by year
- 2026: 47 · 2025: 53 · 2024: 55 · 2023: 35 · 2022: 29 · 2021: 8
- FWCI
- 11.93
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (R01CA190294, T32HL7627-35, T32CA251062, T32 CA009172, 5 P30 CA06516, S10OD018522, S10OD026880)
- NCI NIH (K08CA222657)
- Topics
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- small cell lung cancer, cellular plasticity, MHC class I upregulation, immune checkpoint blockade, EZH2 inhibition, neuroendocrine differentiation, epigenetic reprogramming, antigen presentation, CD8+ T cells, tumor immunogenicity, combination immunotherapy
- MeSH terms
- Cell Plasticity, Animals, Disease Models, Animal, Humans, Lung Neoplasms, Cohort Studies, Mice, Small Cell Lung Carcinoma, Electronic Health Records
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
