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Open Access 01-07-2018 | Original Article

Regulatory T cells control endothelial chemokine production and migration of T cells into intestinal tumors of APC^min/+ mice

Authors: Paulina Akeus, Louis Szeponik, Filip Ahlmanner, Patrik Sundström, Samuel Alsén, Bengt Gustavsson, Tim Sparwasser, Sukanya Raghavan, Marianne Quiding-Järbrink

Published in: Cancer Immunology, Immunotherapy | Issue 7/2018

Abstract

Tumor-infiltrating lymphocytes are crucial for anti-tumor immunity. We have previously shown that regulatory T cells (Treg) are able to reduce T-cell transendothelial migration in vitro and accumulation of effector T cells in intestinal tumors in vivo. Treg depletion also resulted in increased levels of the chemokines CXCL9 and CXCL10 specifically in the tumors. In this study, we investigated the mechanisms for Treg mediated suppression of T-cell migration into intestinal tumors in the APC^min/+ mouse model. By breeding APC^min/+ mice with DEREG mice, which harbour a high affinity diphtheria toxin receptor under the control of the FOXP3 promoter, we were able to deplete Treg in tumor-bearing mice. Using adoptive transfer experiments, we could document a markedly increased migration of T cells specifically into Treg depleted tumors, and that Treg depletion results in increased production of the CXCR3 ligand CXCL10 from endothelial cells in the tumors. Furthermore, we were able to demonstrate that T cells use CXCR3 to migrate into intestinal tumors. In addition, human colon adenocarcinomas express high levels of mRNA CXCR3 ligands and tumor endothelial cells produce CXCL9 and CXCL10 ex vivo. In conclusion, this study demonstrates that Treg reduce endothelial CXCL10 production, inhibit T-cell migration into tumors and that CXCR3 mediated signalling is crucial for lymphocyte accumulation in intestinal tumors. Thus, immunotherapy aimed at Treg depletion may be effective by increasing not only T effector cell activity, but also their accumulation in tumors.

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Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray F (2017) Global patterns and trends in colorectal cancer incidence and mortality. Gut 66:683–691. https://doi.org/10.1136/gutjnl-2015-310912 CrossRefPubMed

Weitz J, Moritz K, Jurgen D, Thomas H, Galle PR, Buchler MW (2005) Colorectal cancer. Lancet 365:153–165. https://doi.org/10.1016/S0140-6736(05)17706-X CrossRefPubMed

Schell MJ, Yang M, Teer JK, Lo FY, Madan A, Coppola D, Monteiro ANA, Nebozhyn MV, Yue B, Loboda A, Bien-Willner GA, Greenawalt DM, Yeatman TJ (2016) A multigene mutation classification of 468 colorectal cancers reveals a prognostic role for APC. Nat Commun 7:11743. https://doi.org/10.1038/ncomms11743 CrossRefPubMedPubMedCentral

Fodde R, Smits R, Clevers H (2001) APC, signal transduction and genetic instability in colorectal cancer. Nat rev Cancer 1:55–67. https://doi.org/10.1038/35094067 CrossRefPubMed

Moser AR, Mattes EM, Dove WF, Lindstrom MJ, Haag JD, Gould MN (1993) ApcMin, a mutation in the murine Apc gene, predisposes to mammary carcinomas and focal alveolar hyperplasias. Proc Natl Acad Sci 90:8977–8981CrossRefPubMedPubMedCentral

Koudougou C, Bonneville M, Matysiak-Budnik T, Touchefeu Y (2013) Antitumoural immunity in colorectal cancer—current and potential future implications in clinical practice. Aliment Pharmacol Ther 38:3–15. https://doi.org/10.1111/apt.12337 CrossRefPubMed

Le Gouvello S, Bastuji-Garin S, Aloulou N, Mansour H, Chaumette M-T, Berrehar F, Seikour A, Charachon A, Karoui M, Leroy K, Farcet J-P, Sobhani I (2008) High prevalence of Foxp3 and IL17 in MMR-proficient colorectal carcinomas. Gut 57:772–779. https://doi.org/10.1136/gut.2007.123794 CrossRefPubMed

Michel S, Benner A, Tariverdian M, Wentzensen N, Hoefler P, Pommerencke T, Grabe N, Knebel Doeberitz von M, Kloor M (2008). High density of FOXP3-positive T cells infiltrating colorectal cancers with microsatellite instability. Br J Cancer 99:1867–1873. https://doi.org/10.1038/sj.bjc.6604756 CrossRefPubMedPubMedCentral

Svensson H, Olofsson V, Lundin S, Yakkala C, Björck S, Börjesson L, Gustavsson B, Quiding-Järbrink M (2012) Accumulation of CCR4⁺ CTLA-4hi FOXP3⁺ CD25hi regulatory T cells in colon adenocarcinomas correlate to reduced activation of conventional T cells. PloS One 7:e30695. https://doi.org/10.1371/journal.pone.0030695.t001 CrossRefPubMedPubMedCentral

10.

Gounaris E, Blatner NR, Dennis K, Magnusson F, Gurish MF, Strom TB, Beckhove P, Gounari F, Khazaie K (2009) T-regulatory cells shift from a protective anti-inflammatory to a cancer-promoting proinflammatory phenotype in polyposis. Cancer Res 69:5490–5497. https://doi.org/10.1158/0008-5472.CAN-09-0304 CrossRefPubMedPubMedCentral

11.

Akeus P, Langenes V, Mentzer von A, Yrlid U, Sjöling Å, Saksena P, Raghavan S, Quiding-Järbrink M (2014) Altered chemokine production and accumulation of regulatory T cells in intestinal adenomas of APC^Min/+ mice. Cancer Immunol Immunother 8:807–819. https://doi.org/10.1007/s00262-014-1555-6 CrossRef

12.

Sundström P, Stenstad H, Langenes V, Ahlmanner F, Theander L, Ndah TG, Fredin K, Börjesson L, Gustavsson B, Bastid J, Quiding-Järbrink M (2016) Regulatory T cells from colon cancer patients inhibit effector T-cell migration through an adenosine-dependent mechanism. Cancer Immunol Res 4:183–193. https://doi.org/10.1158/2326-6066.CIR-15-0050 CrossRefPubMed

13.

Frey DM, Droeser RA, Viehl CT, Zlobec I, Lugli A, Zingg U, Oertli D, Kettelhack C, Terracciano L, Tornillo L (2010) High frequency of tumor-infiltrating FOXP3⁺ regulatory T cells predicts improved survival in mismatch repair-proficient colorectal cancer patients. Int J Cancer 126:2635–2643. https://doi.org/10.1002/ijc.24989 PubMedCrossRef

14.

Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D, Platell C, Iacopetta B (2009) Tumor-infiltrating FOXP3⁺ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 27:186–192. https://doi.org/10.1200/JCO.2008.18.7229 CrossRefPubMed

15.

Ling KL, Pratap SE, Bates GJ, Singh B, Mortensen NJ, George BD, Warren BF, Piris J, Roncador G, Fox SB, Banham AH, Cerundolo V (2007) Increased frequency of regulatory T cells in peripheral blood and tumour infiltrating lymphocytes in colorectal cancer patients. Cancer Immun 7:7PubMedPubMedCentral

16.

Saito T, Nishikawa H, Wada H, Nagano Y, Sugiyama D, Atarashi K, Maeda Y, Hamaguchi M, Ohkura N, Sato E, Nagase H, Nishimura J, Yamamoto H, Takiguchi S, Tanoue T, Suda W, Morita H, Hattori M, Honda K, Mori M, Doki Y, Sakaguchi S (2016) Two FOXP3(+)CD4(+) T cell subpopulations distinctly control the prognosis of colorectal cancers. Nat Med 22:679–684. https://doi.org/10.1038/nm.4086 CrossRefPubMed

17.

Blatner NR, Mulcahy MF, Dennis KL, Scholtens D, Bentrem DJ, Phillips JD, Ham S, Sandall BP, Khan MW, Mahvi DM, Halverson AL, Stryker SJ, Boller AM, Singal A, Sneed RK, Sarraj B, Ansari MJ, Oft M, Iwakura Y, Zhou L, Bonertz A, Beckhove P, Gounari F, Khazaie K (2012) Expression of RORγt marks a pathogenic regulatory T cell subset in human colon cancer. Sci Transl Med 4:164ra159. https://doi.org/10.1126/scitranslmed.3004566 CrossRefPubMedPubMedCentral

18.

Tosolini M, Kirilovsky A, Mlecnik B, Fredriksen T, Mauger S, Bindea G, Berger A, Bruneval P, Fridman WH, Pages F, Galon J (2011) Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, Th2, Treg, Th17) in patients with colorectal cancer. Cancer Res 71:1263–1271. https://doi.org/10.1158/0008-5472.CAN-10-2907 CrossRefPubMed

19.

Carman CV, Martinelli R (2015) T lymphocyte-endothelial interactions: emerging understanding of trafficking and antigen-specific immunity. Front Immunol 6:603. https://doi.org/10.3389/fimmu.2015.00603 CrossRefPubMedPubMedCentral

20.

Akeus P, Langenes V, Kristensen J, Mentzer von A, Sparwasser T, Raghavan S, Quiding-Järbrink M (2015) Treg-cell depletion promotes chemokine production and accumulation of CXCR3(+) conventional T cells in intestinal tumors. Eur J immunol 45:1654–1666. https://doi.org/10.1002/eji.201445058 CrossRefPubMed

21.

Billottet C, Quemener C, Bikfalvi A (2013) CXCR3, a double-edged sword in tumor progression and angiogenesis. Biochim Biophys Acta 1836:287–295. https://doi.org/10.1016/j.bbcan.2013.08.002 PubMedCrossRef

22.

Mlecnik B, Tosolini M, Charoentong P, Kirilovsky A, Bindea G, Berger A, Camus M, Gillard M, Bruneval P, Fridman WH, Pagès F, Trajanoski Z, Galon J (2010) Biomolecular network reconstruction identifies T-cell homing factors associated with survival in colorectal cancer. Gastroenterology 138:1429–1440. https://doi.org/10.1053/j.gastro.2009.10.057 CrossRefPubMed

23.

Yang X, Chu Y, Wang Y, Zhang R, Xiong S (2006) Targeted in vivo expression of IFN-gamma-inducible protein 10 induces specific antitumor activity. J Leukoc Biol 80:1434–1444. https://doi.org/10.1189/jlb.0306212 CrossRefPubMed

24.

Sgadari C, Farber JM, Angiolillo AL, Liao F, Teruya-Feldstein J, Burd PR, Yao L, Gupta G, Kanegane C, Tosato G (1997) Mig, the monokine induced by interferon-gamma, promotes tumor necrosis in vivo. Blood 89:2635–2643PubMed

25.

Enarsson K, Lundin BS, Johnsson E, Brezicka T, Quiding-Järbrink M (2007) CD4⁺ CD25 high regulatory T cells reduce T cell transendothelial migration in cancer patients. Eur J immunol 37:282–291. https://doi.org/10.1002/eji.200636183 CrossRefPubMed

26.

Karim BO, Karim DL (2013) Mouse models for colorectal cancer. Am J Cancer Res 3:240PubMedPubMedCentral

27.

Muthuswamy RV, Sundström P, Börjesson L, Gustavsson B, Quiding-Järbrink M (2013) Impaired migration of IgA-secreting cells to colon adenocarcinomas. Cancer Immunol Immunother 62:989–997. https://doi.org/10.1007/s00262-013-1410-1 CrossRefPubMed

28.

Lahl K, Loddenkemper C, Drouin C, Freyer J, Arnason J, Eberl GER, Hamann A, Wagner H, Huehn J, Sparwasser T (2007) Selective depletion of Foxp3⁺ regulatory T cells induces a scurfy-like disease. J Exp Med 204:57–63. https://doi.org/10.1084/jem.20061852 CrossRefPubMedPubMedCentral

29.

Moser AR, Luongo C, Gould KA, McNeley MK, Shoemaker AR, Dove WF (1995) ApcMin: a mouse model for intestinal and mammary tumorigenesis. Eur J cancer 31A:1061–1064CrossRefPubMed

30.

Lee M, Kiefel H, LaJevic MD, Macauley MS, Kawashima H, O’Hara E, Pan J, Paulson JC, Butcher EC (2014) Transcriptional programs of lymphoid tissue capillary and high endothelium reveal control mechanisms for lymphocyte homing. Nat immunol 15:982–995. https://doi.org/10.1038/ni.2983 CrossRefPubMedPubMedCentral

31.

Lundgren A, Stro E, Sjo AS, Lindholm C, Enarsson K, Edebo A, Johnsson E, Suri-payer E, Larsson P, Rudin A, Svennerholm A-M, Lundin BS (2005) Mucosal FOXP3-expressing CD4 ϩ CD25 high regulatory T Cells in Helicobacter pylori-infected patients. Society 73:523–531. https://doi.org/10.1128/IAI.73.1.523 CrossRef

32.

Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4⁺ CD25⁺ regulatory T cells. Nature Immunol 4:330–336. https://doi.org/10.1038/ni904 CrossRef

33.

Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061CrossRefPubMed

34.

Walser TC (2006) Antagonism of CXCR3 inhibits lung metastasis in a murine model of metastatic breast cancer. Cancer Res 66:7701–7707. https://doi.org/10.1158/0008-5472.CAN-06-0709 CrossRefPubMed

35.

Braster R, Bögels M, Beelen RHJ, van Egmond M (2017) The delicate balance of macrophages in colorectal cancer; their role in tumour development and therapeutic potential. Immunobiology 222:21–30. https://doi.org/10.1016/j.imbio.2015.08.011 CrossRefPubMed

36.

Hindley JP, Jones E, Smart K, Bridgeman H, Lauder SN, Ondondo B, Cutting S, Ladell K, Wynn KK, Withers D, Price DA, Ager A, Godkin AJ, Gallimore AM (2012) T cell trafficking facilitated by high endothelial venules is required for tumor control after regulatory T cell depletion. Cancer Res 72:5473–5482. https://doi.org/10.1158/0008-5472.CAN-12-1912 CrossRefPubMedPubMedCentral

37.

Li X, Kostareli E, Suffner J, Garbi N, Hämmerling GJ (2010) Efficient Treg depletion induces T-cell infiltration and rejection of large tumors. Eur J Immunol 40:3325–3335. https://doi.org/10.1002/eji.201041093 CrossRefPubMed

38.

Teng MWL, Ngiow SF, Scheidt von B, McLaughlin N, Sparwasser T, Smyth MJ (2010) Conditional regulatory T-cell depletion releases adaptive immunity preventing carcinogenesis and suppressing established tumor growth. Cancer Res 70:7800–7809. https://doi.org/10.1158/0008-5472.CAN-10-1681 CrossRefPubMed

39.

Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155:1151–1164PubMed

40.

Austrup F, Vestweber D, Borges E, Löhning M, Bräuer R, Herz U, Renz H, Hallmann R, Scheffold A, Radbruch A, Hamann A (1997) P- and E-selectin mediate recruitment of T-helper-1 but not T-helper-2 cells into inflamed tissues. Nature 385:81–83. https://doi.org/10.1038/385081a0 CrossRefPubMed

41.

Gebhardt T, Whitney PG, Zaid A, Mackay LK, Brooks AG, Heath WR, Carbone FR, Mueller SN (2011) Different patterns of peripheral migration by memory CD4⁺ and CD8⁺ T cells. Nature 477:216–219. https://doi.org/10.1038/nature10339 CrossRefPubMed

42.

Groom JR, Richmond J, Murooka TT, Sorensen EW, Sung JH, Bankert K, Andrian von UH, Moon JJ, Mempel TR, Luster AD (2012) CXCR3 chemokine receptor-ligand interactions in the lymph node optimize CD4⁺ T helper 1 cell differentiation. Immunity 37:1091–1103. https://doi.org/10.1016/j.immuni.2012.08.016 CrossRefPubMedPubMedCentral

43.

Jenh C-H, Cox MA, Cui L, Reich E-P, Sullivan L, Chen S-C, Kinsley D, Qian S, Kim SH, Rosenblum S, Kozlowski J, Fine JS, Zavodny PJ, Lundell D (2012) A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection. BMC Immunol 13:2. https://doi.org/10.1186/1471-2172-13-2 CrossRefPubMedPubMedCentral

44.

Xie JH, Nomura N, Lu M, Chen S-L, Koch GE, Weng Y, Rosa R, Di Salvo J, Mudgett J, Peterson LB, Wicker LS, DeMartino JA (2003) Antibody-mediated blockade of the CXCR3 chemokine receptor results in diminished recruitment of T helper 1 cells into sites of inflammation. J Leukoc Biol 73:771–780CrossRefPubMed

45.

Mikucki ME, Fisher DT, Matsuzaki J, Skitzki JJ, Gaulin NB, Muhitch JB, Ku AW, Frelinger JG, Odunsi K, Gajewski TF, Luster AD, Evans SS (2015) Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints. Nat Commun 6:7458. https://doi.org/10.1038/ncomms8458 CrossRefPubMedPubMedCentral

46.

Woods AN, Wilson AL, Srivinisan N, Zeng J, Dutta AB, Peske JD, Tewalt EF, Gregg RK, Ferguson AR, Engelhard VH (2017) Differential expression of homing receptor ligands on tumor-associated vasculature that control CD8 effector T-cell entry. Cancer Immunol Res 5:1062–1073. https://doi.org/10.1158/2326-6066.CIR-17-0190 CrossRefPubMed

47.

Hansson M, Hermansson M, Svensson H, Elfvin A, Hansson L-E, Johnsson E, Sjöling Å, Quiding-Järbrink M (2008) CCL28 is increased in human Helicobacter pylori-induced gastritis and mediates recruitment of gastric immunoglobulin A-secreting cells. Infect Immun 76:3304–3311. https://doi.org/10.1128/IAI.00041-08 CrossRefPubMedPubMedCentral

48.

Mattsson A, Quiding-Järbrink M, Lönroth H, Hamlet A, Ahlstedt I, Svennerholm A (1998) Antibody-secreting cells in the stomachs of symptomatic and asymptomatic Helicobacter pylori-infected subjects. Infect Immun 66:2705–2712PubMedPubMedCentral

49.

Sierro F, Biben C, Martinez-Munoz L, Mellado M, Ransohoff RM, Li M, Woehl B, Leung H, Groom J, Batten M, Harvey RP, Martinez-A C, Mackay CR, Mackay F (2007) Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12/SDF-1 receptor, CXCR7. PNAS 104:14759–14764. https://doi.org/10.1073/pnas.0702229104 CrossRefPubMedPubMedCentral

50.

Wang L-L, Chen P, Luo S, Li J, Liu K, Hu H-Z, Wei Y-Q (2009) CXC-chemokine-ligand-10 gene therapy efficiently inhibits the growth of cervical carcinoma on the basis of its anti-angiogenic and antiviral activity. Biotechnol Appl Biochem 53:209–216. https://doi.org/10.1042/BA20090012 PubMedCrossRef

51.

Campanella GSV, Colvin RA, Luster AD (2010) CXCL10 can inhibit endothelial cell proliferation independently of CXCR3. PloS one 5:e12700. https://doi.org/10.1371/journal.pone.0012700 CrossRefPubMedPubMedCentral

Title: Regulatory T cells control endothelial chemokine production and migration of T cells into intestinal tumors of APCmin/+ mice
Authors: Paulina Akeus
Louis Szeponik
Filip Ahlmanner
Patrik Sundström
Samuel Alsén
Bengt Gustavsson
Tim Sparwasser
Sukanya Raghavan
Marianne Quiding-Järbrink
Publication date: 01-07-2018
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 7/2018
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-018-2161-9

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