Top

Published in:

01-06-2009 | Original Article

Adoptive transfer of HER2/neu-specific T cells expanded with alternating gamma chain cytokines mediate tumor regression when combined with the depletion of myeloid-derived suppressor cells

Authors: Johanna K. Morales, Maciej Kmieciak, Laura Graham, Marta Feldmesser, Harry D. Bear, Masoud H. Manjili

Published in: Cancer Immunology, Immunotherapy | Issue 6/2009

Abstract

Adoptive immunotherapy (AIT) using ex vivo-expanded HER-2/neu-specific T cells has shown initial promising results against disseminated tumor cells in the bone marrow. However, it has failed to promote objective responses against primary tumors. We report for the first time that alternating gamma chain cytokines (IL-2, IL-7 and IL-15) ex vivo can expand the neu-specific lymphocytes that can kill breast tumors in vitro. However, the anti-tumor efficacy of these neu-specific T cells was compromised by the increased levels of myeloid-derived suppressor cells (MDSC) during the premalignant stage in FVBN202 transgenic mouse model of breast carcinoma. Combination of AIT with the depletion of MDSC, in vivo, resulted in the regression of neu positive primary tumors. Importantly, neu-specific antibody responses were restored only when AIT was combined with the depletion of MDSC. In vitro studies determined that MDSC caused inhibition of T cell proliferation in a contact-dependent manner. Together, these results suggest that combination of AIT with depletion or inhibition of MDSC could lead to the regression of mammary tumors.

Allen SD, Garrett JT, Rawale SV, Jones AL, Phillips G, Forni G, Morris JC, Oshima RG, Kaumaya PT (2007) Peptide vaccines of the HER-2/neu dimerization loop are effective in inhibiting mammary tumor growth in vivo. J Immunol 179(1):472–482PubMed

Bernhard H, Neudorfer J, Gebhard K, Conrad H, Hermann C, Nährig J, Fend F, Weber W, Busch DH, Peschel C (2008) Adoptive transfer of autologous, HER2-specific, cytotoxic T lymphocytes for the treatment of HER2-overexpressing breast cancer. Cancer Immunol Immunother 57(2):271–280PubMedCrossRef

Bronte V, Zanovello P (2005) Regulation of immune responses by l-arginine metabolism. Nat Rev Immunol 5(8):641–654PubMedCrossRef

Bunt SK, Sinha P, Clements VK, Leips J, Ostrand-Rosenberg S (2006) Inflammation induces myeloid-derived suppressor cells that facilitate tumor progression. J Immunol 176(1):284–290PubMed

Chin CS, Graham LJ, Hamad GG, George KR, Bear HD (2001) Bryostatin/ionomycin-activated T cells mediate regression of established tumors. J Surg Res 98(2):108–115PubMedCrossRef

Chin CS, Miller CH, Graham L, Parviz M, Zacur S, Patel B, Duong A, Bear HD (2004) Bryostatin 1/ionomycin (B/I) ex vivo stimulation preferentially activates L-selectinlow tumor-sensitized lymphocytes. Int Immunol 16(9):1283–1294PubMedCrossRef

Curigliano G, Spitaleri G, Pietri E, Rescigno M, De Braud F, Cardillo A, Munzone E, Rocca A, Bonizzi G, Brichard V, Orlando L, Goldhirsch A (2006) Breast cancer vaccines: a clinical reality or fairy tale? Ann Oncol 17(5):750–762PubMedCrossRef

Dang Y, Knutson KL, Goodell V, Goodell V, dela Rosa C, Salazar LG, Higgins D, Childs J, Disis ML (2007) Tumor antigen-specific T-cell expansion is greatly facilitated by in vivo priming. Clin Cancer Res 13(6):1883–1891PubMedCrossRef

Delano MJ, Scumpia PO, Weinstein JS, Coco D, Nagaraj S, Kelly-Scumpia KM, O’Malley KA, Wynn JL, Antonenko S, Al-Quran SZ, Swan R, Chung CS, Atkinson MA, Ramphal R, Gabrilovich DI, Reeves WH, Ayala A, Phillips J, Laface D, Heyworth PG, Clare-Salzler M, Moldawer LL (2007) MyD88-dependent expansion of an immature GR-1(+) CD11b(+) population induces T cell suppression and Th2 polarization in sepsis. J Exp Med 204(6):1463–1474PubMedCrossRef

10.

Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ (2008) Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother 57(2):271–280

11.

Dela Cruz JS, Lau SY, Ramirez EM, De Giovanni C, Forni G, Morrison SL, Penichet ML (2003) Protein vaccination with the HER2/neu extracellular domain plus anti-HER2/neu antibody-cytokine fusion proteins induces a protective anti-HER2/neu immune response in mice. Vaccine 21(13–14):1317–1326PubMedCrossRef

12.

Emens LA, Reilly RT, Jaffee EM (2005) Breast cancer vaccines: maximizing cancer treatment by tapping into host immunity. Endocr Relat Cancer 12(1):1–17PubMedCrossRef

13.

Ezernitchi AV, Vaknin I, Cohen-Daniel L, Levy O, Manaster E, Halabi A, Pikarsky E, Shapira L, Baniyash M (2006) TCR zeta down-regulation under chronic inflammation is mediated by myeloid suppressor cells differentially distributed between various lymphatic organs. J Immunol 177(7):4763–4772PubMed

14.

Gabrilovich D (2004) Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat Rev Immunol 4(12):941–952PubMedCrossRef

15.

Gabrilovich DI, Velders MP, Sotomayor EM, Kast WM (2001) Mechanism of immune dysfunction in cancer mediated by immature Gr-1+ myeloid cells. J Immunol 166(9):5398–5406PubMed

16.

Gallina G, Dolcetti L, Serafini P, De Santo C, Marigo I, Colombo MP, Basso G, Brombacher F, Borello I, Zanovello P, Bicciato S, Bronte V (2006) Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. J Clin Invest 116(10):2777–2790PubMedCrossRef

17.

Goni O, Alcaide P, Fresno M (2002) Immunosuppression during acute Trypanosoma cruzi infection: involvement of Ly6G (Gr1(+))CD11b(+)immature myeloid suppressor cells. Int Immunol 14(10):1125–1134PubMedCrossRef

18.

Guy CT, Webster MA, Schaller M, Parsons TJ, Cardiff RD, Muller WJ (1992) Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci USA 89(22):10578–10582PubMedCrossRef

19.

Habibi M, Kmieciak M, Graham L, Morales JK, Bear HD, Manjili MH (2008) Radiofrequency thermal ablation of breast tumors combined with intralesional administration of IL-7 and IL-15 augments anti-tumor immune responses and inhibits tumor development and metastasis. Breast Cancer Res Treat

20.

Haux J, Johnsen AC, Steinkjer B, Egeberg K, Sundan A, Espevik T (1999) The role of interleukin-2 in regulating the sensitivity of natural killer cells for Fas-mediated apoptosis. Cancer Immunol Immunother 48(2–3):139–146PubMedCrossRef

21.

Huster KM, Busch V, Schiemann M, Linkemann K, Kerksiek KM, Wagner H, Busch DH (2004) Selective expression of IL-7 receptor on memory T cells identifies early CD40L-dependent generation of distinct CD8 + memory T cell subsets. Proc Natl Acad Sci USA 101(15):5610–5615PubMedCrossRef

22.

Kaech SM, Tan JT, Wherry EJ, Konieczny BT, Surh CD, Ahmed R (2003) Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nat Immunol 4(12):1191–1198PubMedCrossRef

23.

Kmieciak M, Knutson KL, Dumur CI, Manjili MH (2007) HER-2/neu antigen loss and relapse of mammary carcinoma are actively induced by T cell-mediated anti-tumor immune responses. Eur J Immunol 37(3):675–685PubMedCrossRef

24.

Kmieciak M, Morales JK, Morales J, Bolesta E, Grimes M, Manjili MH (2008) Danger signals and nonself entity of tumor antigen are both required for eliciting effective immune responses against HER-2/neu positive mammary carcinoma: implications for vaccine design. Cancer Immunol Immunother 57(9):1391–1398PubMedCrossRef

25.

Knutson KL, Almand B, Dang Y, Disis ML (2004) Neu antigen-negative variants can be generated after neu-specific antibody therapy in neu transgenic mice. Cancer Res 64(3):1146–1151PubMedCrossRef

26.

Ko HJ, Kim YJ, Kim YS, Chang WS, Ko SY, Chang SY, Sakaguchi S, Kang CY (2007) A combination of chemoimmunotherapies can efficiently break self-tolerance and induce antitumor immunity in a tolerogenic murine tumor model. Cancer Res 67(15):7477–7486PubMedCrossRef

27.

Kusmartsev SA, Li Y, Chen SH (2000) Gr-1+ myeloid cells derived from tumor-bearing mice inhibit primary T cell activation induced through CD3/CD28 costimulation. J Immunol 165(2):779–785PubMed

28.

Mazzoni A, Bronte V, Visintin A, Spitzer JH, Apolloni E, Serafini P, Zanovello P, Segal DM (2002) Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. J Immunol 168(2):689–695PubMed

29.

Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, Royal RE, Topalian SL, Kammula US, Restifo NP, Zheng Z, Nahvi A, de Vries CR, Rogers-Freezer LJ, Mavroukakis SA, Rosenberg SA (2006) Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314(5796):126–129PubMedCrossRef

30.

Mueller YM, Makar V, Bojczuk PM, Witek J, Katsikis PD (2003) IL-15 enhances the function and inhibits CD95/Fas-induced apoptosis of human CD4+ and CD8+ effector-memory T cells. Int Immunol 15(1):49–58PubMedCrossRef

31.

Nagaraj S, Gupta K, Pisarev V, Kinarsky L, Sherman S, Kang L, Herber DL, Schneck J, Gabrilovich DI (2007) Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat Med 13(7):828–835PubMedCrossRef

32.

Ochoa AC, Zea AH, Hernandez C, Rodriguez PC (2007) Arginase, prostaglandins, and myeloid-derived suppressor cells in renal cell carcinoma. Clin Cancer Res 13(2):721s–726sPubMedCrossRef

33.

Refaeli Y, Van Parijs L, London CA, Tschopp J, Abbas AK (1998) Biochemical mechanisms of IL-2-regulated Fas-mediated T cell apoptosis. Immunity 8(5):615–623PubMedCrossRef

34.

Rodriguez PC, Hernandez CP, Quiceno D, Dubinett SM, Zabaleta J, Ochoa JB, Gilbert J, Ochoa AC (2005) Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma. J Exp Med 202(7):931–939PubMedCrossRef

35.

Rodriguez PC, Quiceno DG, Zabaleta J, Ortiz B, Zea AH, Piazuelo MB, Delgado A, Correa P, Brayer J, Sotomayor EM, Antonia S, Ochoa JB, Ochoa AC (2004) Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res 64(16):5839–5849PubMedCrossRef

36.

Sabel MS, Arora A, Su G, Chang AE (2006) Adoptive immunotherapy of breast cancer with lymph node cells primed by cryoablation of the primary tumor. Cryobiology 53(3):360–366PubMedCrossRef

37.

Sakai K, Yokote H, Murakami-Murofushi K, Tamura T, Saijo N, Nishio K (2007) Pertuzumab, a novel HER dimerization inhibitor, inhibits the growth of human lung cancer cells mediated by the HER3 signaling pathway. Cancer Sci 98(9):1498–1503PubMedCrossRef

38.

Schluns KS, Lefrancois L (2003) Cytokine control of memory T-cell development and survival. Nat Rev Immunol 3(4):269–279PubMedCrossRef

39.

Serafini P, Borrello I, Bronte V (2006) Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. Semin Cancer Biol 16(1):53–65PubMedCrossRef

40.

Stoklasek TA, Schluns KS, Lefrancois L (2006) Combined IL-15/IL-15Ralpha immunotherapy maximizes IL-15 activity in vivo. J Immunol 177(9):6072–6080PubMed

41.

Tuttle TM, Inge TH, Bethke KP, McCrady CW, Pettit GR, Bear HD (1992) Activation and growth of murine tumor-specific T-cells which have in vivo activity with bryostatin 1. Cancer Res 52(3):548–553PubMed

42.

Waldmann TA (2006) The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol 6(8):595–601PubMedCrossRef

43.

Weng NP, Liu K, Catalfamo M, Li Y, Henkart PA (2002) IL-15 is a growth factor and an activator of CD8 memory T cells. Ann N Y Acad Sci 975:46–56PubMedCrossRef

44.

Worschech A, Kmieciak M, Knutson KL, Bear HD, Szalay AA, Wang E, Marincola FM, Manjili MH (2008) Signatures associated with rejection or recurrence in HER-2/neu-positive mammary tumors. Cancer Res 68(7):2436–2446PubMedCrossRef

45.

Young MR, Lathers DM (1999) Myeloid progenitor cells mediate immune suppression in patients with head and neck cancers. Int J Immunopharmacol 21(4):241–252PubMedCrossRef

46.

Zea AH, Rodriguez PC, Atkins MB, Hernandez C, Signoretti S, Zabaleta J, McDermott D, Quiceno D, Youmans A, O’Neill A, Mier J, Ochoa AC (2005) Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res 65(8):3044–3048PubMed

47.

Zheng SG, Wang J, Wang P, Gray JD, Horwitz DA (2007) IL-2 is essential for TGF-beta to convert naive CD4+ CD25- cells to CD25+ Foxp3+ regulatory T cells and for expansion of these cells. J Immunol 178(4):2018–2027PubMed

48.

Zhou J, Zhong Y (2004) Breast cancer immunotherapy. Cell Mol Immunol 1(4):247–255PubMed

Title: Adoptive transfer of HER2/neu-specific T cells expanded with alternating gamma chain cytokines mediate tumor regression when combined with the depletion of myeloid-derived suppressor cells
Authors: Johanna K. Morales
Maciej Kmieciak
Laura Graham
Marta Feldmesser
Harry D. Bear
Masoud H. Manjili
Publication date: 01-06-2009
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 6/2009
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-008-0609-z

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 6/2009

Focal adhesion kinase as an immunotherapeutic target

Treatment of advanced metastasized breast cancer with bone marrow-derived tumour-reactive memory T cells: a pilot clinical study

The immunosuppressive tumor microenvironment in hepatocellular carcinoma

HM1.24 (CD317) is a novel target against lung cancer for immunotherapy using anti-HM1.24 antibody

Low representation of Fc receptor-like 1–5 molecules in leukemic cells from Iranian patients with acute lymphoblastic leukemia

Chronic lymphocytic leukemia (CLL) cells genetically modified to express B7-1, ICAM-1, and LFA-3 confer APC capacity to T cells from CLL patients

Keynote webinar | Spotlight on antibody–drug conjugates in cancer