Journal Article
. 2009 Feb; 15(3):1052-8.
doi: 10.1158/1078-0432.CCR-08-1296.

Increased intratumoral FOXP3-positive regulatory immune cells during interleukin-2 treatment in metastatic renal cell carcinoma

Hanne Krogh Jensen 1 Frede Donskov  Marianne Nordsmark  Niels Marcussen  Hans von der Maase  
Affiliations
  • PMID: 19188179
  •     38 citations

Abstract

Purpose: The administration of interleukin-2 (IL-2) may increase the frequency of peripherally circulating FOXP3-positive regulatory immune cells, thus potentially compromising this treatment option for patients with metastatic renal cell carcinoma. The impact of IL-2-based therapy on the accumulation of FOXP3-positive immune cells in the tumor microenvironment in metastatic renal cell carcinoma is unknown.

Experimental Design: Baseline (n = 58) and on-treatment (n = 42) tumor core biopsies were prospectively obtained from patients with clear cell metastatic renal cell carcinoma before and during IL-2-based immunotherapy. Immunohistochemical expression of FOXP3 was estimated by stereological counting technique and correlated with other immune cell subsets and overall survival.

Results: A significant increase in absolute intratumoral FOXP3-positive immune cells was observed comparing baseline (median 23 cells/mm2; range, 0-183) and on-treatment biopsies (median, 89 cells/mm2; range, 11-388; P < 0.001). The relative increase in individual patients was median 4.7-fold, range 0.3 to 230. FOXP3-positive cells were positively correlated with CD3-positive, CD4-positive, and CD8-positive tumor-infiltrating immune cells at baseline and during treatment (P < 0.05 in all comparisons). All patients achieving high numbers (>180 cells/mm2) of on-treatment FOXP3-positive intratumoral immune cells were dead within 22 months (n = 11), whereas patients with low numbers (<180 cells/mm2) of on-treatment FOXP3-positive cells (n = 31) had a 5-year survival rate of 19% (hazard ratio, 2.2; confidence interval, 1.03-4.5; P = 0.043). All long-term survivors were characterized by low-baseline FOXP3-positive cells and a modest absolute rise in FOXP3-positive cells.

Conclusion: Intratumoral FOXP3-positive regulatory immune cells significantly increased during IL-2-based immunotherapy, and high numbers of on-treatment FOXP3-positive cells were correlated with poor prognosis in patients with metastatic renal cell carcinoma.

Successful immunotherapy with IL-2/anti-CD40 induces the chemokine-mediated mitigation of an immunosuppressive tumor microenvironment.
Jonathan M Weiss, Timothy C Back, +8 authors, Robert H Wiltrout.
Proc Natl Acad Sci U S A, 2009 Nov 07; 106(46). PMID: 19892741    Free PMC article.
The role of regulatory T cells in cancer.
Tai-You Ha.
Immune Netw, 2010 Feb 17; 9(6). PMID: 20157609    Free PMC article.
Immunotherapeutic modulation of the suppressive liver and tumor microenvironments.
Tim Chan, Robert H Wiltrout, Jonathan M Weiss.
Int Immunopharmacol, 2011 Jan 19; 11(7). PMID: 21241810    Free PMC article.
Review.
Therapeutic vaccines in renal cell carcinoma.
Thomas Schwaab, Marc S Ernstoff.
Therapy, 2011 Aug 27; 4(8). PMID: 21869865    Free PMC article.
In vivo expansion of naïve CD4+ CD25(high) FOXP3+ regulatory T cells in patients with colorectal carcinoma after IL-2 administration.
Marc Beyer, Beatrix Schumak, +7 authors, Joachim L Schultze.
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Modulation of CXCR3 ligand secretion by prostaglandin E2 and cyclooxygenase inhibitors in human breast cancer.
Holger Bronger, Sara Kraeft, +5 authors, Manfred Schmitt.
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The immune contexture in human tumours: impact on clinical outcome.
Wolf Herman Fridman, Franck Pagès, Catherine Sautès-Fridman, Jérôme Galon.
Nat Rev Cancer, 2012 Mar 16; 12(4). PMID: 22419253
Highly Cited. Review.
Regulatory T-cells and associated pathways in metastatic renal cell carcinoma (mRCC) patients undergoing DC-vaccination and cytokine-therapy.
Adrian Schwarzer, Benita Wolf, +11 authors, Marc S Ernstoff.
PLoS One, 2012 Nov 03; 7(10). PMID: 23118856    Free PMC article.
Suppression, subversion and escape: the role of regulatory T cells in cancer progression.
K Oleinika, R J Nibbs, G J Graham, A R Fraser.
Clin Exp Immunol, 2012 Dec 04; 171(1). PMID: 23199321    Free PMC article.
Review.
Trial watch: Prognostic and predictive value of the immune infiltrate in cancer.
Laura Senovilla, Erika Vacchelli, +9 authors, Lorenzo Galluzzi.
Oncoimmunology, 2012 Dec 18; 1(8). PMID: 23243596    Free PMC article.
Highly Cited.
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Myoung Jae Kang, Kyoung Min Kim, +6 authors, Kyu Yun Jang.
Transl Oncol, 2013 Jun 05; 6(3). PMID: 23730407    Free PMC article.
Update on vaccine development for renal cell cancer.
Nina Chi, Jodi K Maranchie, Leonard J Appleman, Walter J Storkus.
Open Access J Urol, 2010 Jan 01; 2. PMID: 24198621    Free PMC article.
Review.
PD-1 as an emerging therapeutic target in renal cell carcinoma: current evidence.
Scott S Tykodi.
Onco Targets Ther, 2014 Aug 13; 7. PMID: 25114573    Free PMC article.
Review.
FOXP3+ Tregs: heterogeneous phenotypes and conflicting impacts on survival outcomes in patients with colorectal cancer.
Changhua Zhuo, Ye Xu, +5 authors, Bin Li.
Immunol Res, 2015 Jan 23; 61(3). PMID: 25608795
Review.
Immune signature of tumor infiltrating immune cells in renal cancer.
Katharina Geissler, Paolo Fornara, +3 authors, Dagmar Riemann.
Oncoimmunology, 2015 May 08; 4(1). PMID: 25949868    Free PMC article.
Immunosuppression associated with chronic inflammation in the tumor microenvironment.
Dingzhi Wang, Raymond N DuBois.
Carcinogenesis, 2015 Sep 12; 36(10). PMID: 26354776    Free PMC article.
Highly Cited. Review.
Elevated expression of IFN-inducible CXCR3 ligands predicts poor prognosis in patients with non-metastatic clear-cell renal cell carcinoma.
Weisi Liu, Yidong Liu, +5 authors, Jiejie Xu.
Oncotarget, 2016 Feb 26; 7(12). PMID: 26910919    Free PMC article.
Melittin-MIL-2 fusion protein as a candidate for cancer immunotherapy.
Mingjun Liu, Haitao Wang, +2 authors, Guirong Sun.
J Transl Med, 2016 Jun 02; 14(1). PMID: 27246873    Free PMC article.
The ratio of CD8 to Treg tumor-infiltrating lymphocytes is associated with response to cisplatin-based neoadjuvant chemotherapy in patients with muscle invasive urothelial carcinoma of the bladder.
Alexander S Baras, Charles Drake, +9 authors, Trinity J Bivalacqua.
Oncoimmunology, 2016 Jul 29; 5(5). PMID: 27467953    Free PMC article.
Highly Cited.
Prognostic role of the lymphocyte-to-monocyte ratio in patients undergoing resection for nonmetastatic rectal cancer.
Qing-Bin Wu, Meng Wang, +2 authors, Zi-Qiang Wang.
Medicine (Baltimore), 2016 Nov 20; 95(44). PMID: 27858839    Free PMC article.
Efferocytosis creates a tumor microenvironment supportive of tumor survival and metastasis.
David B Vaught, Jamie C Stanford, Rebecca S Cook.
Cancer Cell Microenviron, 2015 Jan 01; 2(1). PMID: 29264372    Free PMC article.
Distribution and prognostic value of tumor‑infiltrating T cells in breast cancer.
Shaoda Meng, Li Li, +3 authors, Kunxian Yang.
Mol Med Rep, 2018 Sep 18; 18(5). PMID: 30221739    Free PMC article.
Targeting tumor cells with antibodies enhances anti-tumor immunity.
Zhichen Sun, Yang-Xin Fu, Hua Peng.
Biophys Rep, 2018 Dec 12; 4(5). PMID: 30533489    Free PMC article.
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Jie Gao, Lingling Wu, Siyang Wang, Xiangmei Chen.
Mediators Inflamm, 2020 Feb 25; 2020. PMID: 32089645    Free PMC article.
Review.
A next-generation tumor-targeting IL-2 preferentially promotes tumor-infiltrating CD8+ T-cell response and effective tumor control.
Zhichen Sun, Zhenhua Ren, +12 authors, Hua Peng.
Nat Commun, 2019 Aug 30; 10(1). PMID: 31462678    Free PMC article.
The Tumor Microenvironment: A Milieu Hindering and Obstructing Antitumor Immune Responses.
Alireza Labani-Motlagh, Mehrnoush Ashja-Mahdavi, Angelica Loskog.
Front Immunol, 2020 Jun 06; 11. PMID: 32499786    Free PMC article.
Review.
Immune-checkpoint molecules on regulatory T-cells as a potential therapeutic target in head and neck squamous cell cancers.
Susumu Suzuki, Tetsuya Ogawa, +7 authors, Toyonori Tsuzuki.
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Prognostic Value of the Neo-Immunoscore in Renal Cell Carcinoma.
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Front Oncol, 2019 Jun 14; 9. PMID: 31192136    Free PMC article.
Clinical Impact of Tumor-Infiltrating Lymphocytes and PD-L1-Positive Cells as Prognostic and Predictive Biomarkers in Urological Malignancies and Retroperitoneal Sarcoma.
Makito Miyake, Shunta Hori, +5 authors, Kiyohide Fujimoto.
Cancers (Basel), 2020 Oct 31; 12(11). PMID: 33121123    Free PMC article.
Review.
Transcriptional regulation of VEGFA expression in T-regulatory cells from breast cancer patients.
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Nondestructive, multiplex three-dimensional mapping of immune infiltrates in core needle biopsy.
Steve Seung-Young Lee, Vytautas P Bindokas, Mark W Lingen, Stephen J Kron.
Lab Invest, 2018 Nov 08; 99(9). PMID: 30401959    Free PMC article.
Reconnaissance of tumor immune microenvironment spatial heterogeneity in metastatic renal cell carcinoma and correlation with immunotherapy response.
A Hajiran, N Chakiryan, +18 authors, B Manley.
Clin Exp Immunol, 2020 Dec 22; 204(1). PMID: 33346915    Free PMC article.
The intra-class heterogeneity of immunophenotyping and immune landscape in oesophageal cancer and clinical implications.
Yujie Xie, Xiaoshun Shi, +4 authors, Wanli Lin.
Ann Med, 2021 Apr 17; 53(1). PMID: 33860722    Free PMC article.
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Int J Mol Sci, 2021 Sep 11; 22(17). PMID: 34502043    Free PMC article.
Review.
CD177 modulates the function and homeostasis of tumor-infiltrating regulatory T cells.
Myung-Chul Kim, Nicholas Borcherding, +32 authors, Weizhou Zhang.
Nat Commun, 2021 Oct 03; 12(1). PMID: 34599187    Free PMC article.
Updates on Immunotherapy and Immune Landscape in Renal Clear Cell Carcinoma.
Myung-Chul Kim, Zeng Jin, +4 authors, Weizhou Zhang.
Cancers (Basel), 2021 Nov 28; 13(22). PMID: 34831009    Free PMC article.
Review.
PANX1 is a potential prognostic biomarker associated with immune infiltration in pancreatic adenocarcinoma: A pan-cancer analysis.
Lingling Bao, Kai Sun, Xuede Zhang.
Channels (Austin), 2021 Nov 20; 15(1). PMID: 34796785    Free PMC article.
Selective delivery of low-affinity IL-2 to PD-1+ T cells rejuvenates antitumor immunity with reduced toxicity.
Zhenhua Ren, Anli Zhang, +5 authors, Yang-Xin Fu.
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