Soluble IL6R expressed by myeloid cells reduces tumor-specific Th1 differentiation and drives tumor progression
Published version of a preprint
Abstract
IL6 produced by tumor cells promotes their survival, conferring a poor prognosis in patients with cancer. IL6 also contributes to immunosuppression of CD4 + T cell-mediated antitumor effects. In this study, we focused on the impact of IL6 trans-signaling mediated by soluble IL6 receptors (sIL6R) expressed in tumor-bearing hosts. Higher levels of sIL6R circulating in blood were observed in tumor-bearing mice, whereas the systemic increase of sIL6R was not prominent in tumor-bearing mice with myeloid cell-specific conditional deletion of IL6R even when tumor cells produced sIL6R. Abundant sIL6R was released by CD11b + cells from tumor-bearing mice but not tumor-free mice. Notably, IL6-mediated defects in Th1 differentiation, T-cell helper activity for tumor-specific CD8 + T cells, and downstream antitumor effects were rescued by myeloid-specific deletion of sIL6R. Expression of the T-cell transcription factor c-Maf was upregulated in CD4 + T cells primed in tumor-bearing mice in an IL6-dependent manner. Investigations with c-Maf loss-of-function T cells revealed that c-Maf activity was responsible for IL6/sIL6R-induced Th1 suppression and defective T-cell-mediated antitumor responses. In patients with cancer, myeloid cell-derived sIL6R was also possibly associated with Th1 suppression and c-Maf expression. Our results argued that increased expression of sIL6R from myeloid cells and subsequent c-Maf induction were adverse events for counteracting tumor-specific Th1 generation. O…
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
Myeloid-derived sIL-6R complexed with IL-6 inhibits Th1 responses through STAT3-induced c-Maf, considered one mechanism by which IL-6 inhibits T-cell immunity against tumors.
“It was shown that myeloid-derived sIL-6R complexed with IL-6 inhibits Th1 responses through STAT3-induced c-Maf. This is considered to be one of mechanisms by which IL-6 inhibits T-cell immunity against tumors (156).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [156]
Cites
Immunity, Inflammation, and Cancer
Grivennikov, S. I., Greten, F. R., & Karin, M. (2010) · Cell · doi:10.1016/j.cell.2010.01.025 · Cited by 10,755 · see citing works
Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia
Maude, S. L., Frey, N., Shaw, P. A., Aplenc, R., Barrett, D. M., Bunin, N. J., Chew, A., Gonzalez, V. E., Zheng, Z., Lacey, S. F., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1407222 · Cited by 5,413 · see citing works
The immune contexture in human tumours: impact on clinical outcome
Fridman, W. H., Pagès, F., Sautès-Fridman, C., & Galon, J. (2012) · Nature reviews. Cancer · doi:10.1038/nrc3245 · Cited by 4,981 · see citing works
DeNardo, D. G., Barreto, J., Andreu, P., Vásquez, L. J., Tawfik, D., Kolhatkar, N. S., & Coussens, L. M. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.06.018 · Cited by 1,340 · see citing works
Melief, C. J. M., van Hall, T., Arens, R., OSSENDORP, F. A., & van der Burg, S. H. (2015) · Journal of Clinical Investigation · doi:10.1172/jci80009 · Cited by 1,182 · see citing works
Teachey, D. T., Lacey, S. F., Shaw, P. A., Melenhorst, J. J., Maude, S. L., Frey, N., Pequignot, E., Gonzalez, V. E., Chen, F., Finklestein, J., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0040 · Cited by 1,102 · see citing works
Lesina, M., Kurkowski, M. U., Ludes, K., Rose-John, S., Treiber, M., Klöppel, G., Yoshimura, A., Reindl, W., Sipos, B., Akira, S., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.03.009 · Cited by 862 · see citing works
Induction of antigen-specific T cell anergy: An early event in the course of tumor progression
Staveley-O’Carroll, K. F., Sotomayor, E. M., Montgomery, J., Borrello, I., Hwang, L., Fein, S., Pardoll, D. M., & Levitsky, H. I. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.3.1178 · Cited by 702 · see citing works
Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses.
Jostock, T., Müllberg, J., Özbek, S., Atreya, R., Blinn, G., Voltz, N., Fischer, M., Neurath, M., & Rose-John, S. (2001) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.2001.01867.x · Cited by 665 · see citing works
Rose‐John, S., Scheller, J., Elson, G., & Jones, S. A. (2006) · Journal of Leukocyte Biology · doi:10.1189/jlb.1105674 · Cited by 647 · see citing works
OSSENDORP, F. A., Mengedé, E., Camps, M. G. M., Filius, R., & Melief, C. J. M. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.187.5.693 · Cited by 609 · see citing works
CD8+ T lymphocyte mobilization to virus-infected tissue requires CD4+ T-cell help
Nakanishi, Y., Lu, B., Gerard, C. J., & Iwasaki, A. (2009) · Nature · doi:10.1038/nature08511 · Cited by 545 · see citing works
Effector T cell plasticity: flexibility in the face of changing circumstances
Murphy, K. M., & Stockinger, B. (2010) · Nature Immunology · doi:10.1038/ni.1899 · Cited by 482 · see citing works
Bos, R., & Sherman, L. A. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-1322 · Cited by 445 · see citing works
Tagawa, Y., Sekikawa, K., & Iwakura, Y. (1997) · The Journal of Immunology · doi:10.4049/jimmunol.159.3.1418 · Cited by 401 · see citing works
Messi, M., Giacchetto, I., Nagata, K., Lanzavecchia, A., Natoli, G., & Sallusto, F. (2002) · Nature Immunology · doi:10.1038/ni872 · Cited by 347 · see citing works
Tatsumi, T., Kierstead, L. S., Ranieri, E., Gesualdo, L., Schena, F. P., Finke, J. H., Bukowski, R. M., Mueller-Berghaus, J., Kirkwood, J. M., Kwok, W. W., et al. (2002) · The Journal of Experimental Medicine · doi:10.1084/jem.20012142 · Cited by 314 · see citing works
Peters, M. J., Jacobs, S., Ehlers, M., Vollmer, P., Müllberg, J., Wolf, E., Brem, G., Büschenfelde, K. H. M. Z., & Rose‐John, S. (1996) · The Journal of Experimental Medicine · doi:10.1084/jem.183.4.1399 · Cited by 276 · see citing works
TH2-Polarized CD4+ T Cells and Macrophages Limit Efficacy of Radiotherapy
Shiao, S. L., Ruffell, B., DeNardo, D. G., Faddegon, B., Park, C. C., & Coussens, L. M. (2015) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-14-0232 · Cited by 254 · see citing works
Wehbe, H., Henson, R., Meng, F., Mize-Berge, J., & Patel, T. C. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-2130 · Cited by 224 · see citing works
Dorff, T., Goldman, B., Pinski, J., Mack, P., Lara, P., Veldhuizen, P. V., Quinn, D., Vogelzang, N., Thompson, I., & Hussain, M. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-3122 · Cited by 219 · see citing works
IL-6 Trans-Signaling in Formation and Progression of Malignant Ascites in Ovarian Cancer
Lo, C.-W., Chen, M., Hsiao, M., Wang, S., Chen, C., Hsiao, S., Chang, J., Lai, T., Rose‐John, S., Kuo, M., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-1496 · Cited by 193 · see citing works
Redmond, W. L., Linch, S. N., & Kasiewicz, M. J. (2013) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-13-0031-t · Cited by 167 · see citing works
Tsukamoto, H., Clise-Dwyer, K., Huston, G. E., Duso, D. K., Buck, A. L., Johnson, L. L., Haynes, L., & Swain, S. L. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0910139106 · Cited by 166 · see citing works
Self-citationShariat, S. F., Kattan, M. W., Traxel, E. J., Andrews, B., Zhu, K., Wheeler, T. M., & Slawin, K. M. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-0768-03 · Cited by 166 · see citing works
Cutting Edge: Soluble IL-6R Is Produced by IL-6R Ectodomain Shedding in Activated CD4 T Cells
Briso, E. M., Dienz, O., & Rincón, M. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.11.7102 · Cited by 165 · see citing works
Yoshitake, Y., Fukuma, D., Yuno, A., Hirayama, M., Nakayama, H., Tanaka, T., Nagata, M., Takamune, Y., Kawahara, K., Nakagawa, Y., et al. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-0202 · Cited by 157 · see citing works
Self-citationMiguel, J. F. S., Bladé, J., Shpilberg, O., Grosicki, S., Maloisel, F., Min, C., Zarzuela, M. P., Robak, T., Prasad, S. V. S. S., Goh, Y. T., et al. (2014) · Blood · doi:10.1182/blood-2013-12-546374 · Cited by 144 · see citing works
Cytokines of the γc family control CD4+ T cell differentiation and function
Yamane, H., & Paul, W. E. (2012) · Nature Immunology · doi:10.1038/ni.2431 · Cited by 128 · see citing works
Araki, K. (2002) · Nucleic Acids Research · doi:10.1093/nar/gnf102 · Cited by 124 · see citing works
Self-citationIL-6 Plays a Unique Role in Initiating c-Maf Expression during Early Stage of CD4 T Cell Activation
Yang, Y., Ochando, J., Yopp, A. C., Bromberg, J. S., & Ding, Y. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.5.2720 · Cited by 112 · see citing works
Tumor‐specific CD 4+ T cells maintain effector and memory tumor‐specific CD 8+ T cells
Church, S., Jensen, S. M., Antony, P. A., Restifo, N. P., & Fox, B. A. (2013) · European Journal of Immunology · doi:10.1002/eji.201343718 · Cited by 109 · see citing works
Tsukamoto, H., Senju, S., Matsumura, K., Swain, S. L., & Nishimura, Y. (2015) · Nature Communications · doi:10.1038/ncomms7702 · Cited by 104 · see citing works
Self-citationThe IL-6 feed-forward loop: A driver of tumorigenesis
Chang, Q., Daly, L., & Bromberg, J. (2014) · Seminars in Immunology · doi:10.1016/j.smim.2014.01.007 · Cited by 99 · see citing works
Tsukamoto, H., Nishikata, R., Senju, S., & Nishimura, Y. (2013) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-13-0030 · Cited by 86 · see citing works
Self-citationStephens, O., Zhang, Q., Qu, P., Zhou, Y., Chavan, S. S., Tian, E., Williams, D. R., Epstein, J., Barlogie, B., & Shaughnessy, J. D. (2011) · Blood · doi:10.1182/blood-2011-07-367052 · Cited by 63 · see citing works
Lyon, M. F., Jamieson, R. V., Perveen, R., Glenister, P. H., Griffiths, R., Boyd, Y., Glimcher, L. H., Favor, J., Munier, F. L., & Black, G. C. M. (2003) · Human Molecular Genetics · doi:10.1093/hmg/ddg063 · Cited by 57 · see citing works
Phase II Study of Personalized Peptide Vaccination for Previously Treated Advanced Colorectal Cancer
Kibe, S., Yutani, S., Motoyama, S., Nomura, T., Tanaka, N., Kawahara, A., Yamaguchi, T., Matsueda, S., Komatsu, N., Miura, M., et al. (2014) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-14-0035 · Cited by 55 · see citing works
Interleukin-6 receptor signaling. II. Bio-availability of interleukin-6 in serum.
Gaillard, J., Pugnière, M., Tresca, J., Mani, J. C., Klein, B., & Brochier, J. (1999) · PubMed · Cited by 50 · see citing works
Zelba, H., Weide, B., Martens, A., Derhovanessian, E., Bailur, J. K., Kyzirakos, C., Pflugfelder, A., Eigentler, T., Giacomo, A. M. D., Maio, M., et al. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-1015 · Cited by 42 · see citing works
Tjin, E. P. M., Krebbers, G., Meijlink, K. J., van de Kasteele, W., Rosenberg, E. H., Sanders, J., Nederlof, P. M., van de Wiel, B. A., Haanen, J. B. A. G., Melief, C. J. M., et al. (2014) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-13-0097 · Cited by 35 · see citing works
Hazama, S., Takenouchi, H., Tsunedomi, R., Iida, M., Suzuki, N., Iizuka, N., Inoue, Y., Sakamoto, K., Nakao, M., Shindo, Y., et al. (2014) · PubMed · Cited by 26 · see citing works
Flagged first, then by citations
1 of the 43 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
IL-6 in inflammation, autoimmunity and cancer
Hirano, T. (2021) · International Immunology · doi:10.1093/intimm/dxaa078 · Cited by 1,453 · see citing works
Tsukamoto, H., Fujieda, K., Miyashita, A., Fukushima, S., Ikeda, T., Kubo, Y., Senju, S., Ihn, H., Nishimura, Y., & Oshiumi, H. (2018) · Cancer Research · doi:10.1158/0008-5472.can-18-0118 · Cited by 305 · see citing works
“Chronically elevated levels of pro-inflammatory cytokine, interleukin (IL)-6, which promotes tumor cell survival, is a poor prognostic factor in patients with many types of cancer including melanoma (9,19,20).”
BackgroundMethodInfluentialSelf-citationKitamura, H., Ohno, Y., Toyoshima, Y., Ohtake, J., Homma, S., Kawamura, H., Takahashi, N., & Taketomi, A. (2017) · Cancer Science · doi:10.1111/cas.13332 · Cited by 278 · see citing works
Laino, A. S., Woods, D. M., Vassallo, M., Qian, X., Tang, H., Wind‐Rotolo, M., & Weber, J. S. (2020) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-000842 · Cited by 254 · see citing works
CD8+ T cell-intrinsic IL-6 signaling promotes resistance to anti-PD-L1 immunotherapy
Huseni, M. A., Wang, L., Klementowicz, J. E., Yuen, K. C. Y., Bréart, B., Orr, C., Liu, L.-F., Li, Y., Gupta, V., Li, C., et al. (2023) · Cell Reports Medicine · doi:10.1016/j.xcrm.2022.100878 · Cited by 192 · see citing works
“IL-6 can potentially influence anti-PD-L1 efficacy through severalmechanisms,includingsupportofcancercellfitness, 2,4 inhibition of Th1 responses, 5,8,10 promotion of immunosuppressive myeloid cells, 7,9,40–42 or disruption of conventional dendritic cells (cDCs).”
Immune‐suppressive effects of interleukin‐6 on T‐cell‐mediated anti‐tumor immunity
Tsukamoto, H., Fujieda, K., Senju, S., Ikeda, T., Oshiumi, H., & Nishimura, Y. (2017) · Cancer Science · doi:10.1111/cas.13433 · Cited by 165 · see citing works
“entiation of Th1/Th2 subsets (T-bet, GATA-3), nor the frequencies of Foxp3Treg, RORctTh17, or CXCR5Tfh cells.(17,32) Although the functional requirement of STAT3 for IL-6-mediated Th1 inhibition has been shown,(17) the roles of other components, IL-6-mediated ERK or PI3K activation in modulating Th1 differentiation, r…”
BackgroundResultInfluentialSelf-citationHossain, M. A., Liu, G., Dai, B., Si, Y., Yang, Q., Wazir, J., Birnbaumer, L., & Yang, Y. (2020) · Medicinal Research Reviews · doi:10.1002/med.21727 · Cited by 136 · see citing works
“CTLs.(108) IL‐6 secretion also leads to an increased production of IL‐10, prostaglandin E2 (PGE2), and VEGF, factors contributing to repression of CD8 CTL functions.”
BackgroundZhai, K., Huang, Z., Huang, Q., Tao, W., Fang, X., Zhang, A., Li, X., Stark, G. R., Hamilton, T. A., & Bao, S. (2021) · Nature Cancer · doi:10.1038/s43018-021-00267-9 · Cited by 112 · see citing works
Lopez‐Bergami, P., & Barbero, G. (2020) · Cancer and Metastasis Reviews · doi:10.1007/s10555-020-09878-7 · Cited by 84 · see citing works
“Overexpression of IL-6 in the TME driven mainly by tumor cells and tumor-associated fibroblasts has been reported in many tumor types [106, 144, 145].”
BackgroundRegulatory Mechanisms of Inhibitory Immune Checkpoint Receptors Expression
Curdy, N., Lanvin, O., Laurent, C., Fournié, J., & Franchini, D. (2019) · Trends in Cell Biology · doi:10.1016/j.tcb.2019.07.002 · Cited by 82 · see citing works
Ohno, Y., Toyoshima, Y., Yurino, H., Monma, N., Xiang, H., Sumida, K., Kaneumi, S., Terada, S., Hashimoto, S., Ikeo, K., et al. (2017) · Cancer Science · doi:10.1111/cas.13330 · Cited by 74 · see citing works
Mechanisms of Immunosuppression in Colorectal Cancer
Zhang, Y., Rajput, A., Jin, N. Y., & Wang, J. (2020) · Cancers · doi:10.3390/cancers12123850 · Cited by 81 · see citing works
ADAM17 is required for EGF-R–induced intestinal tumors via IL-6 trans-signaling
Schmidt, S., Schumacher, N., Schwarz, J., Tangermann, S., Kenner, L., Schlederer, M., Sibilia, M. C., Linder, M., Altendorf-Hofmann, A., Knösel, T., et al. (2018) · The Journal of Experimental Medicine · doi:10.1084/jem.20171696 · Cited by 80 · see citing works
“As we have shown, EGF-R stimulation of CD11b-positive colonic myeloid cells led to massive IL-6 induction (Srivatsa et al., 2017), and sIL-6R is generated by these cells (Tsukamoto et al., 2017).”
BackgroundLee, Y. I., Shim, J. E., Kim, J., Lee, W. J., Kim, J. W., Nam, K., & Lee, J. H. (2022) · Burns & Trauma · doi:10.1093/burnst/tkac023 · Cited by 66 · see citing works
“Cytokines upregulated by WNT5A include IL-1, CXCL8 (IL-8), CCL2 (monocyte chemoattractant protein-1; MCP-1) and IL-6 [39], of which IL-6 overexpression by tumor-associated fibroblasts was reported in invasive skin lesions, such as melanoma [48,49].”
Optimizing the manufacturing and antitumour response of CAR T therapy
Liu, Y., Sperling, A. S., Smith, E. L., & Mooney, D. J. (2023) · Nature Reviews Bioengineering · doi:10.1038/s44222-023-00031-x · Cited by 59 · see citing works
The outstanding antitumor capacity of CD4+ T helper lymphocytes
Li, T., Wu, B., Yang, T., Zhang, L., & Jin, K. (2020) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2020.188439 · Cited by 57 · see citing works
Trial Watch: Immunostimulation with recombinant cytokines for cancer therapy
García-Martínez, E., Smith, M. M., Buqué, A., Aranda, F., de la Peña, F. A., Rubio, A. I., Cánovas, M. S., Conesa, M. A. V., Fucikova, J. P., Špíšek, R., et al. (2018) · OncoImmunology · doi:10.1080/2162402x.2018.1433982 · Cited by 56 · see citing works
Tsukamoto, H., Kouwaki, T., & Oshiumi, H. (2020) · iScience · doi:10.1016/j.isci.2020.101520 · Cited by 52 · see citing works
“Total RNAs were extracted from serum EVs of wild-type (WT), IL-6 knockout (KO), and IL-6 receptor (IL6R) KO mice Tsukamoto et al., 2017, and these were subjected to high throughput RNA sequencing (RNA-seq) analysis (Figure 1A).”
BackgroundMethodSelf-citationLuo, P., Wang, Y., Zhao, C., Guo, J., Shi, W., Ma, H., Liu, T., Yan, D., Huo, S., Wang, M., et al. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.173822 · Cited by 42 · see citing works
Shi, Y., Liu, X., Liu, J., Zhang, D., Liu, X., Yuan, Y., Zhou, Q., Gao, X., Chen, M., Xu, Y., et al. (2021) · Translational Lung Cancer Research · doi:10.21037/tlcr-21-710 · Cited by 43 · see citing works
“Elevated level of IL-6 has been observed in various types of cancer such as melanoma (20), ovarian (21), and colorectal cancer (22), and it has been reported to play a role in tumor promotion by expansion and survival of malignant cells, neo-angiogenesis, and inflammation (23-26).”
BackgroundHosseini, M. S., Baghaei, K., Hajivalili, M., Zali, M. R., Ebtekar, M., & Amani, D. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.120234 · Cited by 40 · see citing works
Rojas-Sánchez, G., Cotzomi-Ortega, I., Pazos-Salazar, N. G., Reyes‐Leyva, J., & Maycotte, P. (2019) · Biology · doi:10.3390/biology8040071 · Cited by 32 · see citing works
“Another immunosuppressive effect is mediated by IL-6 secreted from tumor cells, CAFs, and other tumor stromal cells which leads to MDSC recruitment to the tumor microenvironment [89,90].”
BackgroundRocco, J. M., Inglefield, J. R., Yates, B., Lichtenstein, D. A., Wang, Y., Goffin, L., Filipović, D., Schiffrin, E. J., & Shah, N. N. (2023) · Blood Advances · doi:10.1182/bloodadvances.2023010708 · Cited by 28 · see citing works
Soluble receptors in cancer: mechanisms, clinical significance, and therapeutic strategies
Park, E., & Lee, C. (2024) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-01150-6 · Cited by 27 · see citing works
“It has been revealed that IL-6 trans-signaling via sIL-6R derived by myeloid cells attenuates CD4 + T helper type 1 (Th1) cell differentiation in tumor-bearing mice, leading to defective anti-tumor responses 69 .”
BackgroundImmunotherapy in Myeloproliferative Diseases
Braun, L. M., & Zeiser, R. (2020) · Cells · doi:10.3390/cells9061559 · Cited by 28 · see citing works
Lopresti, L., Tatangelo, V., Baldari, C. T., & Patrussi, L. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1418527 · Cited by 25 · see citing works
TA-MSCs, TA-MSCs-EVs, MIF: their crosstalk in immunosuppressive tumor microenvironment
Zhang, Z., Zhou, X., Guo, J. J., Zhang, F., Qian, Y., Wang, G., Duan, M., Wang, Y., Zhao, H., Yang, Z., et al. (2022) · Journal of Translational Medicine · doi:10.1186/s12967-022-03528-y · Cited by 25 · see citing works
Drakaki, A., Powles, T. B., Bamias, A., Martín-Liberal, J., Shin, S. J., Friedlander, T. W., Tosi, D., Park, C. H., Gomez‐Roca, C., Joly, F., et al. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-23-0798 · Cited by 25 · see citing works
Elbehairi, S. E. I., Alfaifi, M. Y., Shati, A. A., Al-Shehri, M., Elshaarawy, R. F. M., & Hafez, H. S. (2020) · Chemical Biology & Drug Design · doi:10.1111/cbdd.13703 · Cited by 24 · see citing works
“Furthermore, chronically elevated levels of proinflammatory cytokine IL-6 promoted tumor cell survival in different types of cancers including melanoma (Tsukamoto et al., 2017).”
BackgroundEmerging Complexity in CD4+T Lineage Programming and Its Implications in Colorectal Cancer
Ditoro, D. F., & Basu, R. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.694833 · Cited by 23 · see citing works
Yu, J., Zhikun, G., & Wang, L. (2023) · Life · doi:10.3390/life13051189 · Cited by 21 · see citing works
Sang, Y. B., Yang, H., Lee, W. S., Lee, S. J., Kim, S., Cheon, J., Kang, B., Kim, C. W., Chon, H. J., & Kim, C. (2022) · Cancers · doi:10.3390/cancers14235985 · Cited by 21 · see citing works
Expression profiles and function of IL6 in polymorphonuclear myeloid-derived suppressor cells
Ibrahim, M. L., Lu, C., Klement, J. D., Redd, P. S., Yang, D., Smith, A. D., & Liu, K. (2020) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-020-02620-w · Cited by 20 · see citing works
Zhang, L., Xu, S., Cheng, X. F., Wu, J., Wang, Y., Gao, W., Bao, J., & Yu, H. (2023) · Pathology - Research and Practice · doi:10.1016/j.prp.2023.154495 · Cited by 20 · see citing works
The role of CD8+ T-cells in colorectal cancer immunotherapy
He, T., Hu, C., Li, S., Fan, Y., Xie, F., Sun, X., Jiang, Q., Chen, W., Jia, Y., & Li, W. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e33144 · Cited by 18 · see citing works
“Furthermore, IL-6 can promote the differentiation of TAMs into the M2-like phenotype, limiting the function of CD8 + T-cells [107,108].”
BackgroundR‐ketorolac ameliorates cancer‐associated cachexia and prolongs survival of tumour‐bearing mice
Chrysostomou, S. E., Eder, S., Pototschnig, I., Mayer, A.-L., Derler, M., Mußbacher, M., Schauer, S., Zhang, D., Yan, D., Liu, G., et al. (2024) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.13422 · Cited by 15 · see citing works
“32 Accordingly, the bene fi cial effect of RK on cancer-induced lymphopenia may partially be mediated by reducing IL-6 concentrations.”
BackgroundAoki, T., Nishida, N., & Kudo, M. (2021) · Journal of Histochemistry & Cytochemistry · doi:10.1369/00221554211056853 · Cited by 14 · see citing works
Na, H., Im, K.-I., Kim, N., Lee, J., Gil, S., Min, G. J., & Cho, S. (2024) · iScience · doi:10.1016/j.isci.2024.109783 · Cited by 13 · see citing works
Babl, N., Voll, F., Martowicz, A., Bruß, C., Maddaloni, M., Schmidl, C., Rehli, M., Loipfinger, S., Strieder, N., Gebhard, C., et al. (2025) · Cancer Letters · doi:10.1016/j.canlet.2025.218209 · Cited by 11 · see citing works
“IL-6 is a key player in the regulation of MDSC activity [64,65], and its targeting enhances T cell responses and ICB efficacy [35 – 39].”
Zhang, Y., Min, Q., Huang, Y., Liu, H.-D., Zhu, Z.-Y., Jiang, F., & Hua, H. (2020) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2020/8274021 · Cited by 11 · see citing works
Rehman, A. U., Olsson, P. O., Khan, N., & Khan, K. A. (2020) · The Journal of Membrane Biology · doi:10.1007/s00232-020-00122-5 · Cited by 10 · see citing works
Suppression of CXCL-1 Could Restore Necroptotic Pathway in Chronic Lymphocytic Leukemia
Zhao, X., Sun, Y., Wei, Z., Jiang, J., Xu, J., & Liu, P. (2020) · OncoTargets and Therapy · doi:10.2147/ott.s256993 · Cited by 10 · see citing works
Cancer Cachexia and Antitumor Immunity: Common Mediators and Potential Targets for New Therapies
Rounis, K., Makrakis, D., Gioulbasanis, I., Ekman, S., Petris, L. D., Mavroudis, D., & Agelaki, S. (2022) · Life · doi:10.3390/life12060880 · Cited by 10 · see citing works
“IL-6 Liver stimulation for inducing an acute phase response [1] Upregulation of transcriptional factors that promote myofibrilar breakdown [1] Exogenous administration of IL-6 in ApcMin/+/IL-6−/− mice resulted to the development of a cachexia phenotype [42] Induction of autophagy in skeletal muscle [1] Clinical studie…”
BackgroundPacholczak‐Madej, R., Kosałka-Węgiel, J., Kuszmiersz, P., Mituś, J. W., Püsküllüoğlu, M., Grela-Wojewoda, A., Korkosz, M., & Bazan‐Socha, S. (2023) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph20064926 · Cited by 10 · see citing works
“However, a chronically elevated level of IL-6 promotes tumor cell survival, is a poor prognostic factor, and may indicate the occurrence of irAEs during ICIs treatment [86,87].”
BackgroundAdaptive resistance in cancer immunotherapy
Yang, K. E., Yang, C., Xiong, K., Hao, J., & Ye, L. (2026) · Cellular and Molecular Immunology · doi:10.1038/s41423-026-01424-9 · Cited by 10 · see citing works
“Other cytokines, such as IL-6, IL-10, TGF-β , and IFNs, are also positively associated with checkpoint expression [259 – 263].”
Low expression of IL6R predicts poor prognosis for lung adenocarcinoma
Sun, G., Wang, T., Shi, M., Zhou, H., Wang, J., Huang, Z., Zhang, H., & Shi, J. (2021) · Annals of Translational Medicine · doi:10.21037/atm-21-36 · Cited by 8 · see citing works
“The sIL6R was initially identified as a receptor involved in IL6 anti-signal transduction, and was later identified as an antiviral protein independent of IL6 (31-33).”
BackgroundTokhanbigli, S., Alavifard, H., Aghdaei, H. A., Zali, M. R., & Baghaei, K. (2022) · Bioimpacts · doi:10.34172/bi.2022.24209 · Cited by 6 · see citing works
Wang, W., Zhou, H., Liu, Y., Ren, J., & Chen, L. (2023) · International Journal of Gynecology & Obstetrics · doi:10.1002/ijgo.14768 · Cited by 5 · see citing works
The “Heater” of “Cold” Tumors–Blocking IL‐6
Pu, W., Ma, C., Wang, B., Zhu, W., & Chen, H. (2024) · Advanced Biology · doi:10.1002/adbi.202300587 · Cited by 4 · see citing works
Bulska-Będkowska, W., Czajka-Francuz, P., Cisoń-Jurek, S., Owczarek, A., Francuz, T., & Chudek, J. (2022) · Journal of Interferon and Cytokine Research · doi:10.1089/jir.2022.0092 · Cited by 2 · see citing works
“Possible sources of elevated serum levels of sIL-6Ra include tumor cells (Singh et al, 1995) and myeloid cells in the tumor microenvironment (Tsukamoto et al, 2017).”
Wang, J., Qian, J., Yang, X., Huang, C., Wei, T., Zhou, J., Zhong, G., Zh, Z., & Zhang, Y. (2026) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-026-03735-1 · Cited by 1 · see citing works
Targeting Inflammation to Control Tissue Fibrosis
Song, W., Sun, W., Wang, Z., Teo, K. Y. C., Cheung, C. M. G., & Wang, X. (2022) · International Journal of Drug Discovery and Pharmacology · doi:10.53941/ijddp.v1i1.206 · Cited by 1 · see citing works
“role in B cells, IL-6 has also been reported in regulating T cell function in a STAT3-dependent manner [70,71].”
BackgroundStatistical Concern Regarding the Relationship of Change in Mucus Plug Score with Airflow Over Time
Ikeda, T., & Tomita, Y. (2022) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202207-1273le
“For example, structural equation modeling, which provides an inspection for analyzing the complex relationships betweenmultiple variables, is useful (3).”
BackgroundSelf-citation
- Authors
- Tsukamoto, H., Fujieda, K., Hirayama, M., Ikeda, T., Yuno, A., Matsumura, K., Fukuma, D., Araki, K., Mizuta, H., Nakayama, H., Senju, S., & Nishimura, Y.
- Affiliations
- Kumamoto University (JP)
- Institute of Resource Development and Analysis, Kumamoto University (JP)
- Venue
- Cancer Research
- Published
- 2017-04-30
- Volume
- 77
- Issue
- 9
- Pages
- 2279-2291
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2590262184
- Cited by
- 53
- References
- 43
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 6 · 2023: 8 · 2022: 8 · 2021: 6 · 2020: 14 · 2019: 2 · 2018: 3 · 2017: 3
- FWCI
- 2.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (16H 06498, 16K07093, 15K19493, 17H04272, 15H04311, 15K11296, 16H06276)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- myeloid cells, Th1 differentiation, c-Maf, CD4+ T cells, CD8+ T cells, tumor immunosuppression, tumor progression, cancer immunotherapy, CD11b+ cells, tumor-bearing mice
- MeSH terms
- Animals, Humans, Neoplasms, CD4-Positive T-Lymphocytes, Interleukin-6, Gene Expression Regulation, Neoplastic, Th1 Cells, Receptors, Interleukin-6, Myeloid Cells, Proto-Oncogene Proteins c-maf, Mice, Molecular Targeted Therapy, Carcinogenesis
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
