The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index.
The ICOS/ICOSL Pathway Is Required for Optimal Antitumor Responses Mediated by Anti–CTLA-4 Therapy
Published version of a preprint
Abstract
The anti-CTL-associated antigen 4 (anti-CTLA-4) antibody ipilimumab is the first agent to show improved survival in a randomized phase III trial that enrolled patients with metastatic melanoma. Studies are ongoing to identify mechanisms that elicit clinical benefit in the setting of anti-CTLA-4 therapy. We previously reported that treated patients had an increase in the frequency of T cells expressing the inducible costimulator (ICOS) molecule, a T-cell-specific molecule that belongs to the CD28/CTLA-4/B7 immunoglobulin superfamily. ICOS and its ligand (ICOSL) have been shown to play diverse roles in T-cell responses such as mediating autoimmunity as well as enhancing the development/activity of regulatory T cells. These seemingly opposing roles have made it difficult to determine whether the ICOS/ICOSL pathway is necessary for antitumor responses. To determine whether the ICOS/ICOSL pathway might play a causal role in the antitumor effects mediated by anti-CTLA-4, we conducted studies in ICOS-sufficient and ICOS-deficient mice bearing B16/BL6 melanoma. We show that ICOS(+) T cells comprised a population of Th1 cytokine producing and tumor antigen-specific effector cells. Furthermore, in the absence of ICOS, antitumor T-cell responses elicited by anti-CTLA-4 are significantly diminished, thereby impairing tumor rejection. Our findings establish that the ICOS/ICOSL pathway is necessary for the optimal therapeutic effect of anti-CTLA-4, thus implicating this pathway as a target for future combinatorial strategies to improve the efficacy of anti-CTLA-4 therapy.
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“ICOS and TIM3 expressions on specific T cells subsets are also related to antitumor immunity.52,53”
From The Diversity of Gut Microbiome is Associated With Favorable Responses to Anti–Programmed Death 1 Immunotherapy in Chinese Patients With NSCLC (2019) · cites this paper as [53]
In the citing paper
“mTORC1 activation has been associated with ICOS expression, a T cell coregulatory receptor seen on tumor-infiltrating T cells that has been associated with clinical response (67).”
From Reimagining IDO Pathway Inhibition in Cancer Immunotherapy via Downstream Focus on the Tryptophan–Kynurenine–Aryl Hydrocarbon Axis (2019) · cites this paper as [67]
In the citing paper
“In addition, the immune monitoring studies performed on the trial highlighted the reverse translational approach and identified ICOS + CD4 T cells as a novel subset of T cells associated with anti-CTLA4 therapy (17,18,171,172).”
From The Next Decade of Immune Checkpoint Therapy (2021) · cites this paper as [171]
Citations
Cites
Improved Survival with Ipilimumab in Patients with Metastatic Melanoma
Hodi, F. S., O'Day, S. J., McDermott, D. F., Weber, R. W., Sosman, J. A., Haanen, J. B., Gonzalez, R., Robert, C., Schadendorf, D., Hassel, J. C., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa1003466 · Cited by 15,155
Control of Regulatory T Cell Development by the Transcription Factor Foxp3
Hori, S., Nomura, T., & Sakaguchi, S. (2003) · Science · doi:10.1126/science.1079490 · Cited by 8,187
Enhancement of Antitumor Immunity by CTLA-4 Blockade
Leach, D. R., Krummel, M. F., & Allison, J. P. (1996) · Science · doi:10.1126/science.271.5256.1734 · Cited by 3,955
CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation.
Krummel, M. F., & Allison, J. P. (1995) · The Journal of experimental medicine · doi:10.1084/jem.182.2.459 · Cited by 2,245 · cited 1×
“Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is the prototypical coinhibitory molecule that opposes CD28mediated costimulation (3-5).”
BackgroundCTLA-4 can function as a negative regulator of T cell activation
Walunas, T. L., Lenschow, D. J., Bakker, C. Y., Linsley, P. S., Freeman, G. J., Green, J. M., Thompson, C. B., & Bluestone, J. A. (1994) · Immunity · doi:10.1016/1074-7613(94)90071-x · Cited by 2,222
Sharpe, A. H., & Freeman, G. J. (2002) · Nature reviews. Immunology · doi:10.1038/nri727 · Cited by 1,759
Phan, G. Q., Yang, J. C., Sherry, R. M., Hwu, P., Topalian, S. L., Schwartzentruber, D. J., Restifo, N. P., Haworth, L. R., Seipp, C. A., Freezer, L. J., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1533209100 · Cited by 1,575
Harding, F., McArthur, J. G., Gross, J. A., Raulet, D. H., & Allison, J. P. (1992) · Nature · doi:10.1038/356607a0 · Cited by 1,558
ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28
Hutloff, A., Dittrich, A. M., Beier, K. C., Eljaschewitsch, B., Kraft, R., Anagnostopoulos, I., & Kroczek, R. A. (1999) · Nature · doi:10.1038/16717 · Cited by 1,482
van Elsas, A., Hurwitz, A. A., & Allison, J. P. (1999) · The Journal of Experimental Medicine · doi:10.1084/jem.190.3.355 · Cited by 1,020 · cited 8×
“ICOSCD8T cells produce IFN-γ upon recognition of tumor antigen and the absence of ICOS results in diminished tumor antigen-specific T cell responses Since CD8 T cells have been shown to play a dominant role in tumor rejection in the B16/BL6 melanoma model treated with anti-CTLA-4 (7-9, 36), we investigated the impact…”
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B7-H Abnormalities in Melanoma and Clinical Relevance
Seliger, B. (2013) · Methods in molecular biology · doi:10.1007/978-1-62703-727-3_19 · Cited by 4
Papadimitriou, M., Liakouli, Z., & PAPADIMITRIOU, C. A. (2021) · Journal of Cancer Metastasis and Treatment · doi:10.20517/2394-4722.2021.138 · Cited by 4
Li, X., Li, J., Zheng, Y. H., Lee, S. J., Zhou, J., Giobbie‐Hurder, A., Butterfield, L. H., Dranoff, G., & Hodi, F. S. (2023) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-22-0702 · Cited by 4
Jamrasi, P., Tazi, M., Zulkifli, N. A. B., Bae, J. H., & Song, W. J. (2024) · The Journal of Physiological Sciences · doi:10.1186/s12576-024-00950-3 · Cited by 3
ICOS Expression as Immunologic Marker in Immune Activating Monoclonal Antibodies
Danielli, R., Cutaia, O., Fazio, C., Bertocci, E., Fonsatti, E., Maio, M., & Calabrò, L. (2016) · Methods in molecular biology · doi:10.1007/978-1-4939-3338-9_13 · Cited by 3
Iyer, K. A., Ivanov, J. M., Tenchov, R., Ralhan, K., Rodríguez, Y., Sasso, J. M., Scott, S. A., & Zhou, Q. A. (2023) · ChemRxiv · doi:10.26434/chemrxiv-2023-bpvfq · Cited by 3
Deciphering immunoregulatory vulnerabilities in human cancers
Gálvez‐Cancino, F., Lladser, Á., & Quezada, S. A. (2022) · Nature Immunology · doi:10.1038/s41590-022-01251-w · Cited by 2
Emerging options for the treatment of melanoma – focus on ipilimumab
Roddie, C., & Peggs, K. S. (2014) · ImmunoTargets and Therapy · doi:10.2147/itt.s43522 · Cited by 2
Hu, X., Liu, C., An, J., Shen, Y., Hu, Y., Jiang, J., Wu, J. H., & Zhang, X. (2016) · Monoclonal Antibodies in Immunodiagnosis and Immunotherapy · doi:10.1089/mab.2015.0059 · Cited by 1
Diller, M. L., & Kudchadkar, R. R. (2015) · doi:10.1093/med/9780199971015.003.0006 · Cited by 1
Sainson, R. C. A., Thotakura, A. K., Kosmač, M., Borhis, G., Parveen, N., Kimber, R., Carvalho, J., Henderson, S. C., Pryke, K. L., Okell, T., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/771493 · Cited by 1
Individualisierte Tumortherapie und Status quo beim Melanom
Bauer, S., Schmidberger, H., & Trefzer, U. (2012) · Onkologie · doi:10.1159/000337697
Tumor-Produced Immune Regulating Factors
Andersen, M. H., Becker, J. C., & Straten, P. T. (2013) · Springer eBooks · doi:10.1007/978-94-007-6217-6_11
Conference Scene: Immune Signatures in the Tumor and Beyond
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IN FOCUS A Systems Biology Approach to Personalizing Therapeutic Combinations
Kwong, L. N., Heffernan, T. P., & Chin, L. (2013)
Marker Utility for Combination Therapy
Simeone, E., Grimaldi, A. M., & Ascierto, P. A. (2013) · Methods in molecular biology · doi:10.1007/978-1-62703-727-3_7
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Ranganath, S. H., & Nguyen, A. (2016) · Springer eBooks · doi:10.1007/978-3-319-29827-6_7
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Scutti, J. A. B. (2016) · Journal of Cancer Prevention & Current Research · doi:10.15406/jcpcr.2016.06.00216
Bendriss‐Vermare, N., Gourdin, N., Vey, N., Faget, J., Sisirak, V., Labidi‐Galy, S. I., Mercier, I. L., Goutagny, N., Puisieux, I., Ménétrier‐Caux, C., et al. (2017) · Springer eBooks · doi:10.1007/978-3-319-62431-0_8
Bartkowiak, T. (2017) · Digital Commons-TMC (Texas Medical Center)
Defining and targeting combination immunotherapies in mouse models of cancer
Demane, F., & Demane, D. F. (2019) · UCL Discovery (University College London)
Immune Checkpoints are Important Therapeutic Targets in Cancer Immunotherapy
Ratna, A., Mukherjee, S., & Das, S. K. (2021) · Cancer Science & Research · doi:10.33425/2639-8478.1079
Simonaggio, A., & Marabelle, A. (2018) · Bulletin du Cancer · doi:10.1016/s0007-4551(18)30397-7
Sharma, P., Anandhan, S., Siddiqui, B. A., Goswami, S., Subudhi, S. K., Gao, J., Peggs, K. S., Quezada, S. A., & Allison, J. P. (2022) · Wiley eBooks · doi:10.1002/9781119000822.hfcm068.pub2
Self-citationGavrielatou, N., Economopoulou, P., & Psyrri, A. K. (2022) · Cancer immunotherapy · doi:10.1007/13905_2022_30
Silva, D. M. D., Enserro, D. M., Mayadev, J., Skeate, J. G., Matsuo, K., Pham, H. Q., Lankes, H. A., Moxley, K. M., Ghamande, S. A., Lin, Y. G., et al. (2023) · doi:10.1158/1078-0432.c.6529304
Sainson, R. C. A., Thotakura, A. K., Kosmač, M., Borhis, G., Parveen, N., Kimber, R., Carvalho, J., Henderson, S. J., Pryke, K. L., Okell, T., et al. (2023) · doi:10.1158/2326-6066.c.6550282
Redmond, W. L., Linch, S. N., & Kasiewicz, M. J. (2023) · doi:10.1158/2326-6066.c.6548227.v1
Kawanabe-Matsuda, H., Takeda, K., Nakamura, M., Makino, S., Karasaki, T., Kakimi, K., Nishimukai, M., Ohno, T., Omi, J., Kano, K., et al. (2023) · doi:10.1158/2159-8290.c.6549610
Synovial inducible costimulator is correlated with severity in knee osteoarthritis
Yang, L., Ma, J., Niu, P., Zhang, B., & Wang, Z. (2023) · Scandinavian Journal of Immunology · doi:10.1111/sji.13315
Yadavilli, S., Waight, J. D., Brett, S. J., Bi, M., Zhang, T., Liu, Y.-B., Ellis, C. E., Turner, D. C., Hahn, A., Shi, H., et al. (2023) · doi:10.1158/2767-9764.c.6749780
Wang, Y., Ding, S., Wang, Y. F., Xie, H., Liu, S. S., Chen, H., Wu, D., Xie, Y., Wen, X., Zhu, Y. Z., et al. (2025) · MedComm · doi:10.1002/mco2.70450
Ralser, D. J., Herr, E., de Vos, L., Kulcsár, Z., Zarbl, R., Klümper, N., Gielen, G. H., Maas, A. P., Hoffmann, F., Dietrich, J., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23273359
Gu, J.-Y., Qi, Q., Mao, X., Cong, R., Sun, Y., Tang, X.-Y., Guan, X., Wang, J., Yu, M.-X., Wang, S., et al. (2025) · Breast Cancer Research · doi:10.1186/s13058-025-02205-4
La souris humanisée : modèle d'étude de l'immunothérapie anti-cancer
Rochère, P. D. L. (2018) · theses.fr (ABES) · doi:10.70675/62c63415zab1az40e4z8c1fz0b5580505c4f
Normal and pathological functions of the T cell signaling protein, THEMIS, in CD4+ T cells
Yang, C. (2021) · theses.fr (ABES) · doi:10.70675/59026c4ezea46z4241za55azd03232fac9cd
Shukshin, A. A., Rubinstein, A., Головкин, А. С., Моисеева, О. М., & Kudryavtsev, I. V. (2026) · Medical academic journal · doi:10.17816/maj641690
Liu, W., Ren, X., Zhang, Y., Yue, Q., Chen, X., Zhou, D., Li, X., Xin, Q., Kong, L., Wu, H., et al. (2026) · BMC Medicine · doi:10.1186/s12916-026-04994-7
Metadata
- Authors
- Fu, T., He, Q., & Sharma, P.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- ORCID
- Sharma, Padmanee
- Venue
- Cancer Research
- Published
- 2011-08-11
- Volume
- 71
- Issue
- 16
- Pages
- 5445-5454
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2141756397
- Cited by
- 243
- References
- 48
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 15 · 2023: 25 · 2022: 19 · 2021: 23 · 2020: 19 · 2019: 14 · 2018: 20 · 2017: 16 · 2016: 14 · 2015: 17 · 2014: 13 · 2013: 21 · 2012: 11
- FWCI
- 7.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- 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 blockade, ipilimumab, metastatic melanoma, B16-BL6 melanoma, antitumor T-cell responses, tumor rejection, CTLA-4, regulatory T cells, autoimmunity
- MeSH terms
- Animals, Enzyme-Linked Immunosorbent Assay, Melanoma, Experimental, Mice, Inbred C57BL, Proteins, Antigens, CD, Lymphocytes, Tumor-Infiltrating, Mice, CTLA-4 Antigen, Inducible T-Cell Co-Stimulator Ligand
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