Early B cell changes predict autoimmunity following combination immune checkpoint blockade
Open accessAbstract
Combination checkpoint blockade (CCB) targeting inhibitory CTLA4 and PD1 receptors holds promise for cancer therapy. Immune-related adverse events (IRAEs) remain a major obstacle for the optimal application of CCB in cancer. Here, we analyzed B cell changes in patients with melanoma following treatment with either anti-CTLA4 or anti-PD1, or in combination. CCB therapy led to changes in circulating B cells that were detectable after the first cycle of therapy and characterized by a decline in circulating B cells and an increase in CD21lo B cells and plasmablasts. PD1 expression was higher in the CD21lo B cells, and B cell receptor sequencing of these cells demonstrated greater clonality and a higher frequency of clones compared with CD21hi cells. CCB induced proliferation in the CD21lo compartment, and single-cell RNA sequencing identified B cell activation in cells with genomic profiles of CD21lo B cells in vivo. Increased clonality of circulating B cells following CCB occurred in some patients. Treatment-induced changes in B cells preceded and correlated with both the frequency and timing of IRAEs. Patients with early B cell changes experienced higher rates of grade 3 or higher IRAEs 6 months after CCB. Thus, early changes in B cells following CCB may identify patients who are at increased risk of IRAEs, and preemptive strategies targeting B cells may reduce toxicities in these patients.
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
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?
Rarely, irAEs may be fatal, including about 0.35% of those treated with anti-PD-1/PD-L1 and 1.2% treated with combination therapy.
“Rarely, some events may be fatal, including ~0.35% of those treated with anti-PD-1/PD-L1, and 1.2% treated with combination therapy.24”
From Endocrine toxicities of immune checkpoint inhibitors (2021) · cites this paper as [24]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review
Wanchoo, R., Karam, S., Uppal, N. N., Barta, V. S., Deray, G., Devoe, C., Launay‐Vacher, V., Jhaveri, K. D., & on behalf of Cancer and Kidney International Network Workgroup on Immune Checkpoint Inhibitors (2017) · American Journal of Nephrology · doi:10.1159/000455014 · Cited by 15,314 · see citing works
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma
Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Grob, J. J., Cowey, C. L., Lao, C. D., Schadendorf, D., Dummer, R., Smylie, M., Rutkowski, P., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1504030 · Cited by 8,157 · see citing works
Self-citationNivolumab plus Ipilimumab in Advanced Melanoma
Wolchok, J. D., Kluger, H., Callahan, M. K., Postow, M. A., Rizvi, N. A., Lesokhin, A. M., Segal, N. H., Ariyan, C. E., Gordon, R.-A., Reed, K., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1302369 · Cited by 4,230 · cited 1× · see citing works
“org Volume 128 Number 2 February 2018 Introduction Combination checkpoint blockade (CCB) therapy with antiCTLA4 and anti-PD1 for the treatment of patients with melanoma leads to higher response rates and progression-free survival compared with treatment with either drug alone (1, 2).”
BackgroundSelf-citationSafety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination
Boutros, C., Tarhini, A. A., Routier, É., Lambotte, O., Ladurie, F. L. R., Carbonnel, F., Izzeddine, H., Marabelle, A., Champiat, S., Berdelou, A., et al. (2016) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.58 · Cited by 1,090 · see citing works
Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4
Kuehn, H. S., Ouyang, W., Lo, B., Deenick, E. K., Niemela, J. E., Avery, D. T., Schickel, J., Tran, D. Q., Stoddard, J. L., Zhang, Y., et al. (2014) · Science · doi:10.1126/science.1255904 · Cited by 854 · see citing works
Beck, K. E., Blansfield, J. A., Tran, K. Q., Feldman, A. L., Hughes, M. S., Royal, R. E., Kammula, U. S., Topalian, S. L., Sherry, R. M., Kleiner, D., et al. (2006) · Journal of Clinical Oncology · doi:10.1200/jco.2005.04.5716 · Cited by 833 · see citing works
Iwama, S., De Remigis, A., Callahan, M. K., Slovin, S. F., Wolchok, J. D., & Caturegli, P. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3008002 · Cited by 715 · see citing works
Osorio, J. C., Ni, A., Chaft, J. E., Pollina, R., Kasler, M. K., Stephens, D., Rodriguez, C., Cambridge, L., Rizvi, H., Wolchok, J. D., et al. (2017) · Annals of Oncology · doi:10.1093/annonc/mdw640 · Cited by 659 · see citing works
Tipton, C. M., Fucile, C., Darce, J. R., Chida, A. S., Ichikawa, T., Gregoretti, I. V., Schieferl, S. M., Hom, J., Jenks, S. A., Feldman, R. J., et al. (2015) · Nature Immunology · doi:10.1038/ni.3175 · Cited by 584 · see citing works
Coinhibitory Pathways in the B7-CD28 Ligand-Receptor Family
Schildberg, F. A., Klein, S. R., Freeman, G. J., & Sharpe, A. H. (2016) · Immunity · doi:10.1016/j.immuni.2016.05.002 · Cited by 537 · see citing works
Complement receptor 2/CD21− human naive B cells contain mostly autoreactive unresponsive clones
Isnardi, I., Ng, Y.-S., Menard, L. C., Meyers, G., Saadoun, D., Srdanovic, I., Samuels, J., Berman, J., Buckner, J. H., Cunningham‐Rundles, C., et al. (2010) · Blood · doi:10.1182/blood-2009-09-243071 · Cited by 475 · see citing works
Combination Therapy with Anti–CTLA-4 and Anti–PD-1 Leads to Distinct Immunologic Changes In Vivo
Das, R., Verma, R., Sznol, M., Boddupalli, C. S., Gettinger, S. N., Kluger, H. M., Callahan, M. K., Wolchok, J. D., Halaban, R., Dhodapkar, M. V., et al. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1401686 · Cited by 465 · see citing works
Self-citationCXCL13 is a plasma biomarker of germinal center activity
Havenar‐Daughton, C., Lindqvist, M., Heit, A., Wu, J. E., Reiss, S. M., Kendric, K. J., Bélanger, S., Kasturi, S. P., Landais, E., Akondy, R. S., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1520112113 · Cited by 343 · see citing works
Sznol, M., Postow, M. A., Davies, M. J., Pavlick, A. C., Plimack, E. R., Shaheen, M. F., Veloski, C., & Robert, C. (2017) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2017.06.002 · Cited by 290 · see citing works
Self-citationAutoimmune Bullous Skin Disorders with Immune Checkpoint Inhibitors Targeting PD-1 and PD-L1
Naidoo, J., Schindler, K., Querfeld, C., BUSAM, K. J., Cunningham, J. D., Page, D. B., Postow, M. A., Weinstein, A., Lucas, A. S., Ciccolini, K. T., et al. (2016) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-15-0123 · Cited by 287 · see citing works
Lau, D., Lan, L. Y.-L., Andrews, S. F., Henry, C., Rojas, K. T., Neu, K. E., Huang, M., Huang, Y., DeKosky, B. J., Palm, A.-K. E., et al. (2017) · Science Immunology · doi:10.1126/sciimmunol.aai8153 · Cited by 251 · see citing works
CD21–/low B cells in human blood are memory cells
Thorarinsdottir, K., Camponeschi, A., Cavallini, N., Grimsholm, O., Jacobsson, L., Gjertsson, I., & Mårtensson, I. (2016) · Clinical & Experimental Immunology · doi:10.1111/cei.12795 · Cited by 93 · see citing works
Rakhmanov, M., Gutenberger, S., Keller, B., et al. (2010) · Blood · doi:10.1182/blood-2010-05-285585 · Cited by 30 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Hallmarks of response, resistance, and toxicity to immune checkpoint blockade
Morad, G., Helmink, B. A., Sharma, P., & Wargo, J. A. (2021) · Cell · doi:10.1016/j.cell.2021.09.020 · Cited by 1,648 · see citing works
The immune contexture and Immunoscore in cancer prognosis and therapeutic efficacy
Bruni, D., Angell, H. K., & Galon, J. (2020) · Nature reviews. Cancer · doi:10.1038/s41568-020-0285-7 · Cited by 1,586 · see citing works
Transfer learning enables predictions in network biology
Theodoris, C. V., Xiao, L., Chopra, A., Chaffin, M. D., Al Sayed, Z. R., Hill, M. C., Mantineo, H., Brydon, E. M., Zeng, Z., Liu, X. S., et al. (2023) · Nature · doi:10.1038/s41586-023-06139-9 · Cited by 1,193 · see citing works
Immune-checkpoint inhibitors: long-term implications of toxicity
Johnson, D. B., Nebhan, C. A., Moslehi, J. J., & Balko, J. M. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00600-w · Cited by 982 · see citing works
Collateral damage: Insulin-dependent diabetes induced with checkpoint inhibitors
Stamatouli, A. M., Quandt, Z., Perdigoto, A. L., Clark, P. L., Kluger, H., Weiss, S. A., Gettinger, S., Sznol, M., Young, A., Rushakoff, R., et al. (2018) · Diabetes · doi:10.2337/dbi18-0002 · Cited by 590 · see citing works
Self-citationEndocrine toxicities of immune checkpoint inhibitors
Wright, J. J., Powers, A. C., & Johnson, D. B. (2021) · Nature Reviews Endocrinology · doi:10.1038/s41574-021-00484-3 · Cited by 441 · see citing works
Wei, S. C., Anang, N.-A. A. S., Sharma, R., Andrews, M. C., Reuben, A., Levine, J. H., Cogdill, A. P., Mancuso, J. J., Wargo, J. A., Pe’er, D., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1821218116 · Cited by 359 · see citing works
Moving towards personalized treatments of immune-related adverse events
Esfahani, K., Elkrief, A., Calabrese, C., Lapointe, R., Hudson, M., Routy, B., Miller, W. H., & Calabrese, L. (2020) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-020-0352-8 · Cited by 351 · see citing works
Johnson, D. B., McDonnell, W. J., Gonzalez-Ericsson, P. I., Al-Rohil, R. N., Mobley, B. C., Salem, J.-E., Wang, D. Y., Sanchez, V., Wang, Y., Chastain, C. A., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0523-2 · Cited by 176 · see citing works
Mechanisms of immune checkpoint inhibitor-mediated liver injury
Shojaie, L., Ali, M., Iorga, A., & Dara, L. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.10.003 · Cited by 98 · see citing works
B cell depletion or absence does not impede anti-tumor activity of PD-1 inhibitors
Damsky, W., Jilaveanu, L., Turner, N., Perry, C., Zito, C., Tomayko, M., Leventhal, J., Herold, K., Meffre, E., Bosenberg, M., et al. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-019-0613-1 · Cited by 78 · see citing works
Self-citationShah, K. P., Song, H., Ye, F., Moslehi, J. J., Balko, J. M., Salem, J.-E., & Johnson, D. B. (2020) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-19-0986 · Cited by 64 · see citing works
Impact of B‐cell‐targeted therapies on cardiovascular disease
Porsch, F., & Binder, C. J. (2019) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.119.311996 · Cited by 29 · see citing works
Intercellular signaling dynamics from a single cell atlas of the biomaterials response
Cherry, C., Maestas, D. R., Han, J., Andorko, J. I., Cahan, P., Fertig, E. J., Garmire, L. X., & Elisseeff, J. H. (2020) · doi:10.1101/2020.07.24.218537
- Authors
- Das, R., Bar, N., Ferreira, M., Newman, A. M., Zhang, L., Bailur, J. K., Bacchiocchi, A., Kluger, H., Wei, W., Halaban, R., Sznol, M., Dhodapkar, M. V., & Dhodapkar, K. M.
- Affiliations
- Yale University (US)
- Institute for Stem Cell Biology and Regenerative Medicine (IN)
- Yale Cancer Center (US)
- Corresponding author
- Dhodapkar, Kavita M.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2018-01-08
- Volume
- 128
- Issue
- 2
- Pages
- 715-720
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC5785243
- OpenAlex
- W2781484625
- Cited by
- 423
- References
- 18
- Citations by year
- 2026: 35 · 2025: 39 · 2024: 52 · 2023: 64 · 2022: 68 · 2021: 54 · 2020: 53 · 2019: 35 · 2018: 20
- FWCI
- 15.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- NIH (CA197603, 1 P50 CA121974)
- 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
- CTLA-4, PD-1, immune-related adverse events, autoimmunity, B cells, CD21low B cells, plasmablasts, melanoma, predictive biomarkers, B cell activation, single-cell RNA sequencing, B-cell depletion
- MeSH terms
- Aged, B-Lymphocytes, Female, Humans, Immune System, Immunotherapy, Leukocytes, Mononuclear, Male, Melanoma, Middle Aged, Phenotype, Risk, Skin Neoplasms, Autoimmunity, Kaplan-Meier Estimate, CTLA-4 Antigen, Programmed Cell Death 1 Receptor
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
