Neoadjuvant PD-1 Immune Checkpoint Blockade Reverses Functional Immunodominance among Tumor Antigen–Specific T Cells
Open accessPublished version of a preprint
Abstract
Purpose: Surgical resection of primary tumor with regional lymphadenectomy remains the treatment of choice for patients with advanced human papillomavirus–negative head and neck squamous cell carcinoma. However, even when pathologic disease-free margins can be achieved, locoregional and/or distant disease relapse remains high. Perioperative immunotherapy may improve outcomes, but mechanistic data supporting the use of neoadjuvant or adjuvant treatment clinically are sparse. Experimental Design: Two syngeneic models of oral cavity carcinoma with defined T-cell antigens were treated with programmed death receptor 1 (PD-1) mAb before or after surgical resection of primary tumors, and antigen-specific T-cell responses were explored with functional and in vivo challenge assays. Results: We demonstrated that functional immunodominance developed among T cells targeting multiple independent tumor antigens. T cells specific for subdominant antigens expressed greater levels of PD-1. Neoadjuvant, but not adjuvant, PD-1 immune checkpoint blockade broke immunodominance and induced T-cell responses to dominant and subdominant antigens. Using tumors lacking the immunodominant antigen as a model of antigen escape, neoadjuvant PD-1 immune checkpoint blockade induced effector T-cell immunity against tumor cells lacking immunodominant but retaining subdominant antigen. When combined with complete surgical excision, neoadjuvant PD-1 immune checkpoint blockade led to formation of immunologic memory capable of preventing engraftment of tumors lacking the immunodominant but retaining subdominant antigen. Conclusions: Together, these results implicate PD-1 expression by T cells in the mechanism of functional immunodominance among independent T-cell clones within a progressing tumor and support the use of neoadjuvant PD-1 immune checkpoint blockade in patients with surgically resectable carcinomas.
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?
The study illustrates immunodominance, in which T cells targeting a dominant clone expand mainly at the expense of T cells reactive to subdominant clones.
“This study highlights the concept of immunodominance, whereby T cells targeting a dominant clone are primarily expanded at the expense of T cells reactive to subdominant clones.”
From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [110]
The Discussion supports the existence of immunodominance: dominant-antigen-specific T cells suppress responses to subdominant antigens. But it explicitly says the study did not demonstrate differential clonal expansion; instead, it found functional suppression of subdominant T cells associated with PD-1 expression. That contradicts the claim that dominant T cells primarily expand at their expense. (LLM, conf=0.89)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredNeoadjuvant but not adjuvant administration of immune checkpoint inhibitors preserves T cell clones reactive to less-common immunogenic clones in mouse models of head and neck squamous cell carcinoma.
“neoadjuvant but not adjuvant administration of ICIs preserves T cell clones reactive to less-common immunogenic clones in mouse models of head and neck squamous cell carcinoma110.”
From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [110]
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
PD-1 blockade induces responses by inhibiting adaptive immune resistance
Tumeh, P. C., Harview, C. L., Yearley, J. H., Shintaku, I. P., Taylor, E. J. M., Robert, L., Chmielowski, B., Spasic, M., Henry, G., Ciobanu, V., et al. (2014) · Nature · doi:10.1038/nature13954 · Cited by 6,609 · cited 1× · see citing works
“PD-1 immune checkpoint blockade rescues the function of tumor antigen–specific T cells that are suppressed by PD-1 expression (16).”
BackgroundCancer Immunoediting: Integrating Immunity’s Roles in Cancer Suppression and Promotion
Schreiber, R. D., Old, L. J., & Smyth, M. J. (2011) · Science · doi:10.1126/science.1203486 · Cited by 6,474 · see citing works
Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck
Ferris, R. L., Blumenschein, G., Fayette, J., Guigay, J., Colevas, A. D., Licitra, L., Harrington, K., Kasper, S., Vokes, E. E., Even, C., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1602252 · Cited by 5,101 · see citing works
Bernier, J., Domenge, C., Özşahin, M., Matuszewska, K., Lefebvre, J., Greiner, R. H., Giralt, J., Maingon, P., Rolland, F., Bolla, M., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa032641 · Cited by 3,195 · see citing works
Fundamental Mechanisms of Immune Checkpoint Blockade Therapy
Wei, S. C., Duffy, C. R., & Allison, J. P. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-0367 · Cited by 3,088 · see citing works
An immunogenic personal neoantigen vaccine for patients with melanoma
Ott, P. A., Hu, Z., Keskin, D. B., Shukla, S. A., Sun, J., Bozym, D. J., Zhang, W., Luoma, A., Giobbie-Hurder, A., Peter, L., et al. (2017) · Nature · doi:10.1038/nature22991 · Cited by 2,936 · see citing works
Molecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection
Wherry, E. J., Ha, S.-J., Kaech, S. M., Haining, W. N., Sarkar, S., Kalia, V., Subramaniam, S., Blattman, J. N., Barber, D. L., & Ahmed, R. (2007) · Immunity · doi:10.1016/j.immuni.2007.09.006 · Cited by 2,103 · see citing works
Neoadjuvant PD-1 Blockade in Resectable Lung Cancer
Forde, P. M., Chaft, J. E., Smith, K. N., Anagnostou, V., Cottrell, T. R., Hellmann, M. D., Zahurak, M., Yang, S. C., Jones, D. R., Broderick, S., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1716078 · Cited by 2,099 · see citing works
Seiwert, T. Y., Burtness, B., Mehra, R., Weiss, J., Berger, R., Eder, J. P., Heath, K., McClanahan, T., Lunceford, J., Gause, C., et al. (2016) · The Lancet Oncology · doi:10.1016/s1470-2045(16)30066-3 · Cited by 1,745 · cited 10× · see citing works
“org Clin Cancer Res; 26(3) February 1, 2020 683”
BackgroundInfluentialMolecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection
Wherry, E. J., Ha, S., Kaech, S. M., Haining, W. N., Sarkar, S., Kalia, V., Subramaniam, S., Blattman, J. N., Barber, D. L., & Ahmed, R. (2007) · Immunity · doi:10.1016/j.immuni.2007.11.006 · Cited by 1,355 · see citing works
PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors
Gros, A., Robbins, P. F., Yao, X., Li, Y. F., Turcotte, S., Tran, E., Wunderlich, J. R., Mixon, A., Farid, S., Dudley, M. E., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci73639 · Cited by 1,113 · see citing works
Rescue of exhausted CD8 T cells by PD-1–targeted therapies is CD28-dependent
Kamphorst, A. O., Wieland, A., Nasti, T., Yang, S., Zhang, R., Barber, D. L., Konieczny, B. T., Daugherty, C. Z., Koenig, L., Yu, K., et al. (2017) · Science · doi:10.1126/science.aaf0683 · Cited by 1,015 · see citing works
Improved Efficacy of Neoadjuvant Compared to Adjuvant Immunotherapy to Eradicate Metastatic Disease
Liu, J., Blake, S. J., Yong, M. C. R., Harjunpää, H., Ngiow, S. F., Takeda, K., Young, A., O'Donnell, J. S., Allen, S., Smyth, M. J., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0577 · Cited by 894 · see citing works
Memory CD8 T-Cell Differentiation during Viral Infection
Wherry, E. J., & Ahmed, R. (2004) · Journal of Virology · doi:10.1128/jvi.78.11.5535-5545.2004 · Cited by 858 · see citing works
The Transcription Factor NFAT Promotes Exhaustion of Activated CD8 + T Cells
Martinez, G. J., Pereira, R. M., Äijö, T., Kim, E. Y., Marangoni, F., Pipkin, M. E., Togher, S., Heissmeyer, V., Zhang, Y. C., Crotty, S., et al. (2015) · Immunity · doi:10.1016/j.immuni.2015.01.006 · Cited by 857 · cited 1× · see citing works
“TCR ligation drives PD-1 expression on antigen-experienced T cells through NFAT signaling (27).”
BackgroundA single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma
Huang, A. C. C., Orlowski, R. J., Xu, X., Mick, R., George, S. M., Yan, P., Manne, S., Kraya, A., Wubbenhorst, B. S., Dorfman, L. M., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0357-y · Cited by 680 · see citing works
Tumor-draining lymph nodes are pivotal in PD-1/PD-L1 checkpoint therapy
Fransen, M. F., Schoonderwoerd, M. J. A., Knopf, P., Camps, M. G. M., Hawinkels, L. J. A. C., Kneilling, M., van Hall, T., & OSSENDORP, F. A. (2018) · JCI Insight · doi:10.1172/jci.insight.124507 · Cited by 430 · see citing works
Hinrichs, C., Borman, Z. A., Cassard, L., Gattinoni, L., Spolski, R., Yu, Z.-Y., Sanchez-Perez, L., Muranski, P., Kern, S., Logun, C., et al. (2009) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0907448106 · Cited by 407 · see citing works
PD-1 Blockade Expands Intratumoral Memory T Cells
Ribas, A., Shin, D. S., Zaretsky, J., Frederiksen, J., Cornish, A., Avramis, E., Seja, E., Kivork, C., Siebert, J., Kaplan-Lefko, P., et al. (2016) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-15-0210 · Cited by 405 · cited 1× · see citing works
“Briefly, recombinant H-2K and b2-microglobulin were produced in BL21-CodonPlus (DE3)-RIPL Escherichia coli (Agilent) and purified from inclusion bodies by size-exclusion fast protein liquid chromatography (FPLC) as previously described (21).”
MethodHuang, A. Y.-C., Gulden, P. H., Woods, A. S., Thomas, M. C., Tong, C., Wang, W., Engelhard, V. H., Pasternack, G. R., Cotter, R. J., Hunt, D. F., et al. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.18.9730 · Cited by 386 · see citing works
High Avidity CTLs for Two Self-Antigens Demonstrate Superior In Vitro and In Vivo Antitumor Efficacy
Zeh, H. J., Perry-Lalley, D. M., Dudley, M. E., Rosenberg, S. A., & Yang, J. C.-H. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.162.2.989 · Cited by 377 · see citing works
Danna, E. A., Sinha, P., Gilbert, M., Clements, V. K., Pulaski, B. A., & Ostrand‐Rosenberg, S. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-2646 · Cited by 372 · see citing works
CD8 T cell dysfunction during chronic viral infection
Shin, H., & Wherry, E. J. (2007) · Current Opinion in Immunology · doi:10.1016/j.coi.2007.06.004 · Cited by 346 · see citing works
Primary Chemotherapy in Resectable Oral Cavity Squamous Cell Cancer: A Randomized Controlled Trial
Licitra, L. F., Grandi, C., Guzzo, M., et al. (2003) · Journal of Clinical Oncology · doi:10.1200/jco.2003.06.146 · Cited by 323 · see citing works
Endogenous retroviral signatures predict immunotherapy response in clear cell renal cell carcinoma
Smith, C. C., Beckermann, K. E., Bortone, D. S., De Cubas, A. A., Bixby, L. M., Lee, S. J., Panda, A., Ganesan, S., Bhanot, G., Wallen, E. M., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci121476 · Cited by 303 · see citing works
PD‐L1 co‐stimulation contributes to ligand‐induced T cell receptor down‐modulation on CD8+ T cells
Karwacz, K., Bricogne, C., MacDonald, D. C., Vargas, F. A., Bennett, C. L., Collins, M. K., & Escors, D. (2011) · EMBO Molecular Medicine · doi:10.1002/emmm.201100165 · Cited by 267 · see citing works
ERK1/2 Regulation of CD44 Modulates Oral Cancer Aggressiveness
Judd, N. P., Winkler, A. E., Murillo, O., Brotman, J. J., Law, J. H., Lewis, J. S., Dunn, G. P., Bui, J. D., Sunwoo, J. B., & Uppaluri, R. (2011) · Cancer Research · doi:10.1158/0008-5472.can-11-1831 · Cited by 223 · see citing works
Self-citationHung, A. C. F. (1996) · Medical Entomology and Zoology · Cited by 206 · see citing works
Nagaya, T., Friedman, J., Maruoka, Y., Ogata, F., Okuyama, S., Clavijo, P. E., Choyke, P. L., Allen, C. T., & Kobayashi, H. (2019) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-18-0546 · Cited by 163 · see citing works
Self-citationResection of Solid Tumors Reverses T Cell Defects and Restores Protective Immunity
Salvadori, S., Martinelli, G. P., & Zier, K. S. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.4.2214 · Cited by 143 · see citing works
Onken, M. D., Winkler, A. E., Kanchi, K.-L., Chalivendra, V., Law, J. H., Rickert, C. G., Kallogjeri, D., Judd, N. P., Dunn, G. P., Piccirillo, J. F., et al. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-0205 · Cited by 119 · see citing works
Self-citationBroomfield, S., Currie, A. J., der Most, R. G. V., Brown, M. D., van Bruggen, I., Robinson, B. W. S., & Lake, R. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-0328 · Cited by 87 · see citing works
Partridge, M., Brakenhoff, R. H., Phillips, E., et al. (2003) · PubMed · Cited by 82 · see citing works
PD-1 expression conditions T cell avidity within an antigen-specific repertoire
Simon, S., Vignard, V., Florenceau, L., Dréno, B., Khammari, A., Lang, F., & Labarrière, N. (2015) · OncoImmunology · doi:10.1080/2162402x.2015.1104448 · Cited by 73 · see citing works
Batf3+ DCs and type I IFN are critical for the efficacy of neoadjuvant cancer immunotherapy
Liu, J., Rozeman, E. A., O’Donnell, J. S., Allen, S. M., Fanchi, L. F., Smyth, M. J., Blank, C. U., & Teng, M. W. L. (2018) · OncoImmunology · doi:10.1080/2162402x.2018.1546068 · Cited by 70 · see citing works
Memarnejadian, A., Meilleur, C. E., Shaler, C. R., Khazaie, K., Bennink, J. R., Schell, T. D., & Haeryfar, S. M. M. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1700643 · Cited by 64 · see citing works
Seung, S. K., Urban, J. L., & Schreiber, H. W. (1993) · The Journal of Experimental Medicine · doi:10.1084/jem.178.3.933 · Cited by 61 · see citing works
Self-citationSun, L., Moore, E. C., Berman, R. M., Clavijo, P. E., Saleh, A. D., Chen, Z., Waes, C. V., Davies, J., Friedman, J., & Allen, C. T. (2018) · OncoImmunology · doi:10.1080/2162402x.2018.1488359 · Cited by 57 · see citing works
Self-citationSandberg, J. K., Grufman, P., Wolpert, E. Z., et al. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.160.7.3163 · Cited by 53 · see citing works
Making the Most of Cancer Surgery with Neoadjuvant Immunotherapy
Melero, I., Berraondo, P., Rodriguez-Ruiz, M. E., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-1109 · Cited by 49 · see citing works
Stepwise immunologic selection of antigenic variants during tumor growth.
Urban, J. L., Kripke, M. L., & Schreiber, H. W. (1986) · The Journal of Immunology · doi:10.4049/jimmunol.137.9.3036 · Cited by 45 · see citing works
Self-citationZolkind, P., Przybylski, D., Marjanovic, N. D., Nguyễn, L., Lin, T., Johanns, T. M., Alexandrov, A., Zhou, L., Allen, C. T., Miceli, A. P., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.23751 · Cited by 43 · see citing works
Self-citationWortzel, R. D., Urban, J. L., Philipps, C., et al. (1983) · The Journal of Immunology · doi:10.4049/jimmunol.130.5.2461 · Cited by 37 · see citing works
Highly malignant tumor variants retain tumor-specific antigens recognized by T helper cells.
Waes, C. V., Urban, J. L., Rothstein, J. L., et al. (1986) · The Journal of Experimental Medicine · doi:10.1084/jem.164.5.1547 · Cited by 37 · see citing works
Laban, S., Giebel, G., Klümper, N., Schröck, A., Doescher, J., Spagnoli, G., Thierauf, J. C., Theodoraki, M., Remark, R., Gnjatic, S., et al. (2017) · OncoTarget · doi:10.18632/oncotarget.14830 · Cited by 37 · see citing works
Waes, C. V., Monach, P. A., Urban, J. L., Wortzel, R. D., & Schreiber, H. W. (1996) · Tissue Antigens · doi:10.1111/j.1399-0039.1996.tb02575.x · Cited by 35 · see citing works
Self-citationIdentification of Tumoricidal TCRs from Tumor-Infiltrating Lymphocytes by Single-Cell Analysis
Shitaoka, K., Hamana, H., Kishi, H., Hayakawa, Y., Kobayashi, E., Sukegawa, K., Piao, X., Lyu, F., Nagata, T., Sugiyama, D., et al. (2018) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-17-0489 · Cited by 34 · see citing works
Morisada, M. V., Moore, E. C., Hodge, R., Friedman, J., Cash, H. A., Hodge, J. W., Mitchell, J. B., & Allen, C. T. (2017) · Oral Oncology · doi:10.1016/j.oraloncology.2017.06.005 · Cited by 30 · see citing works
Self-citationRowley, D. A., & Stach, R. M. (1993) · The Journal of Experimental Medicine · doi:10.1084/jem.178.3.835 · Cited by 28 · see citing works
Immunological consequences of tumor excision: From active immunity to immunological memory
Bursuker, I., & North, R. J. (1986) · International Journal of Cancer · doi:10.1002/ijc.2910370216 · Cited by 22 · see citing works
Harnessing shared antigens and T-cell receptors in cancer: Opportunities and challenges
Dhodapkar, K. M., & Dhodapkar, M. V. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1608860113 · Cited by 10 · see citing works
How Can Cytoreduction Surgery Improve the Prospects for Cancer Patients Receiving Immunotherapy?
Judy, B. F., & Singhal, S. K. (2012) · Immunotherapy · doi:10.2217/imt.12.121 · Cited by 4 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma
Llovet, J. M., Pinyol, R., Yarchoan, M., Singal, A. G., Marron, T. U., Schwartz, M., Pikarsky, E., Kudo, M., & Finn, R. S. (2024) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-024-00868-0 · Cited by 391 · see citing works
- Authors
- Friedman, J., Moore, E. C., Zolkind, P., Robbins, Y., Clavijo, P. E., Sun, L., Greene, S., Morisada, M. V., Mydlarz, W. K., Schmitt, N., Hodge, J. W., Schreiber, H., Van Waes, C., Uppaluri, R., & Allen, C.
- Affiliations
- National Institutes of Health (US)
- Washington University in St. Louis (US)
- 1Translational Tumor Immunology Program, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland.
- Johns Hopkins University (US)
- University of Chicago (US)
- 6Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland.
- Brigham and Women's Hospital (US)
- Corresponding author
- Allen, Clint
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2020-02-01
- Volume
- 26
- Issue
- 3
- Pages
- 679-689
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC7002203
- OpenAlex
- W2981322953
- Cited by
- 88
- References
- 52
- Citations by year
- 2026: 15 · 2025: 12 · 2024: 19 · 2023: 8 · 2022: 18 · 2021: 7 · 2020: 9
- FWCI
- 3.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH NIDCD (ZIA-DC000087)
- Doris Duke Charitable Foundation (2014194)
- NIH NIDCR (DE027736)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- PD-1 immune checkpoint blockade, head and neck squamous cell carcinoma, neoadjuvant immunotherapy, tumor antigen-specific T cells, antigen escape, immunological memory, surgical resection, lymph node dissection, tumor recurrence
- MeSH terms
- Animals, Antibodies, Monoclonal, Humans, Immunotherapy, Mice, Inbred C57BL, Mouth Neoplasms, T-Lymphocytes, Immunodominant Epitopes, Neoadjuvant Therapy, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Tumor Microenvironment, 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
