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T-helper I immunity, specific for the breast cancer antigen insulin-like growth factor-I receptor (IGF-IR), is associated with increased adiposity

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Abstract

Numerous lines of evidence demonstrate that breast cancer is immunogenic; yet, there are few biologically relevant immune targets under investigation restricting the exploration of vaccines to limited breast cancer subtypes. Insulin-like growth factor-I receptor (IGF-IR) is a promising vaccine candidate since it is overexpressed in most breast cancer subtypes, is part of a dominant cancer growth pathway, and has been validated as a therapeutic target. We questioned whether IGF-IR was immunogenic in cancer patients. IGF-IR-specific IgG antibodies were significantly elevated in early-stage breast cancer patients at the time of diagnosis as compared to volunteer donors (p = 0.04). Predicted T-helper epitopes, derived from the IGF-IR extracellular and transmembrane domains, elicited a significantly higher incidence of Th2 immunity in breast cancer patients as compared to controls (p = 0.01). Moreover, the magnitude of Th2 immunity was greater in breast cancer patients compared to controls (p = 0.02). In contrast, both breast cancer patients and volunteer donors demonstrated a similar incidence of Th1 immunity to IGF-IR domains with the predominant response directed against epitopes in the intracellular domain of the protein. As the incidence of IGF-IR type I immunity was not associated with a breast cancer diagnosis, we questioned whether other factors were contributing to the presence of IGF-IR-specific T-cells in both populations. While age was not associated with Th1 immunity, we observed a significantly greater magnitude of IGF-IR IFN-γ-secreting T-cells in obese subjects as compared to overweight (p < 0.001) or healthy-weight (p = 0.006) subjects, regardless of breast cancer diagnosis. No significant difference was observed for Th2 incidence or magnitude when stratified by age (p = 0.174, p = 0.966, respectively) or body mass index (p = 0.137, p = 0.174, respectively). Our data demonstrate that IGF-IR is a tumor antigen and IGF-IR-specific Th1 immunity may be associated with obesity rather than malignancy.

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References

  1. Sears AK, Perez SA, Clifton GT, Benavides LC, Gates JD, Clive KS, Holmes JP, Shumway NM, Van Echo DC, Carmichael MG, Ponniah S, Baxevanis CN, Mittendorf EA, Papamichail M, Peoples GE (2011) AE37: a novel T-cell-eliciting vaccine for breast cancer. Expert Opin Biol Ther 11:1543–1550

    Article  PubMed  CAS  Google Scholar 

  2. Disis ML, Wallace DR, Gooley TA, Dang Y, Slota M, Lu H, Coveler AL, Childs JS, Higgins DM, Fintak PA, dela Rosa C, Tietje K, Link J, Waisman J, Salazar LG (2009) Concurrent trastuzumab and HER2/neu-specific vaccination in patients with metastatic breast cancer. J Clin Oncol 27:4685–4692

    Article  PubMed  CAS  Google Scholar 

  3. Yerushalmi R, Gelmon KA, Leung S, Gao D, Cheang M, Pollak M, Turashvili G, Gilks BC, Kennecke H (2012) Insulin-like growth factor receptor (IGF-1R) in breast cancer subtypes. Breast Cancer Res Treat 132:131–142

    Article  PubMed  CAS  Google Scholar 

  4. Law JH, Habibi G, Hu K, Masoudi H, Wang MY, Stratford AL, Park E, Gee JM, Finlay P, Jones HE, Nicholson RI, Carboni J, Gottardis M, Pollak M, Dunn SE (2008) Phosphorylated insulin-like growth factor-i/insulin receptor is present in all breast cancer subtypes and is related to poor survival. Cancer Res 68:10238–10246

    Article  PubMed  CAS  Google Scholar 

  5. Litzenburger BC, Creighton CJ, Tsimelzon A, Chan BT, Hilsenbeck SG, Wang T, Carboni JM, Gottardis MM, Huang F, Chang JC, Lewis MT, Rimawi MF, Lee AV (2011) High IGF-IR activity in triple-negative breast cancer cell lines and tumorgrafts correlates with sensitivity to anti-IGF-IR therapy. Clin Cancer Res 17:2314–2327

    Article  PubMed  CAS  Google Scholar 

  6. Lanzavecchia A (1985) Antigen-specific interaction between T and B cells. Nature 314:537–539

    Article  PubMed  CAS  Google Scholar 

  7. Ma Y, Aymeric L, Locher C, Kroemer G, Zitvogel L (2011) The dendritic cell-tumor cross-talk in cancer. Curr Opin Immunol 23:146–152

    Article  PubMed  CAS  Google Scholar 

  8. Disis ML, dela Rosa C, Goodell V, Kuan LY, Chang JC, Kuus-Reichel K, Clay TM, Kim Lyerly H, Bhatia S, Ghanekar SA, Maino VC, Maecker HT (2006) Maximizing the retention of antigen specific lymphocyte function after cryopreservation. J Immunol Methods 308:13–18

    Article  PubMed  CAS  Google Scholar 

  9. Park KH, Gad E, Goodell V, Dang Y, Wild T, Higgins D, Fintak P, Childs J, Dela Rosa C, Disis ML (2008) Insulin-like growth factor-binding protein-2 is a target for the immunomodulation of breast cancer. Cancer Res 68:8400–8409

    Article  PubMed  CAS  Google Scholar 

  10. Goodell V, McNeel D, Disis ML (2008) His-tag ELISA for the detection of humoral tumor-specific immunity. BMC Immunol 9:23

    Article  PubMed  Google Scholar 

  11. Ramduth D, Day CL, Thobakgale CF, Mkhwanazi NP, de Pierres C, Reddy S, van der Stok M, Mncube Z, Nair K, Moodley ES, Kaufmann DE, Streeck H, Coovadia HM, Kiepiela P, Goulder PJ, Walker BD (2009) Immunodominant HIV-1 Cd4 + T cell epitopes in chronic untreated clade C HIV-1 infection. PLoS ONE 4:e5013

    Article  PubMed  Google Scholar 

  12. Guerkov RE, Targoni OS, Kreher CR, Boehm BO, Herrera MT, Tary-Lehmann M, Lehmann PV, Schwander SK (2003) Detection of low-frequency antigen-specific IL-10-producing CD4(+) T cells via ELISPOT in PBMC: cognate vs. nonspecific production of the cytokine. J Immunol Methods 279:111–121

    Article  PubMed  CAS  Google Scholar 

  13. Fluckiger AC, Garrone P, Durand I, Galizzi JP, Banchereau J (1993) Interleukin 10 (IL-10) upregulates functional high affinity IL-2 receptors on normal and leukemic B lymphocytes. J Exp Med 178:1473–1481

    Article  PubMed  CAS  Google Scholar 

  14. Rousset F, Garcia E, Defrance T, Peronne C, Vezzio N, Hsu DH, Kastelein R, Moore KW, Banchereau J (1992) Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes. Proc Natl Acad Sci USA 89:1890–1893

    Article  PubMed  CAS  Google Scholar 

  15. O’Garra A (1998) Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity 8:275–283

    Article  PubMed  Google Scholar 

  16. Ruffatti A, Rossi L, Calligaro A, Del Ross T, Lagni M, Marson P, Todesco S (1990) Autoantibodies of systemic rheumatic diseases in the healthy elderly. Gerontology 36:104–111

    Article  PubMed  CAS  Google Scholar 

  17. Attanasio R, Brasky KM, Robbins SH, Jayashankar L, Nash RJ, Butler TM (2001) Age-related autoantibody production in a nonhuman primate model. Clin Exp Immunol 123:361–365

    Article  PubMed  CAS  Google Scholar 

  18. Tachikawa S, Kawamura T, Kawamura H, Kanda Y, Fujii Y, Matsumoto H, Abo T (2008) Appearance of B220low autoantibody-producing B-1 cells at neonatal and older stages in mice. Clin Exp Immunol 153:448–455

    Article  PubMed  CAS  Google Scholar 

  19. Viardot A, Heilbronn LK, Samocha-Bonet D, Mackay F, Campbell LV, Samaras K (2012) Obesity is associated with activated and insulin resistant immune cells. Diabetes Metab Res Rev 28:447–454

    Article  PubMed  CAS  Google Scholar 

  20. Bäck KAH (2009) Changes in insulin and IGF-I receptor expression during differentiation of human preadipocytes. Growth Horm IGF Res 19:101–111

    Article  PubMed  Google Scholar 

  21. Goodell V, Waisman J, Salazar LG, de la Rosa C, Link J, Coveler AL, Childs JS, Fintak PA, Higgins DM, Disis ML (2008) Level of HER-2/neu protein expression in breast cancer may affect the development of endogenous HER-2/neu-specific immunity. Mol Cancer Ther 7:449–454

    Article  PubMed  CAS  Google Scholar 

  22. Snapper CM, Kehry MR, Castle BE, Mond JJ (1995) Multivalent, but not divalent, antigen receptor cross-linkers synergize with CD40 ligand for induction of Ig synthesis and class switching in normal murine B cells. A redefinition of the TI-2 vs T cell-dependent antigen dichotomy. J Immunol 154:1177–1187

    PubMed  CAS  Google Scholar 

  23. DeNardo DG, Coussens LM (2007) Inflammation and breast cancer. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression. Breast Cancer Res 9:212

    Article  PubMed  Google Scholar 

  24. Aspord C, Pedroza-Gonzalez A, Gallegos M, Tindle S, Burton EC, Su D, Marches F, Banchereau J, Palucka AK (2007) Breast cancer instructs dendritic cells to prime interleukin 13-secreting CD4 + T cells that facilitate tumor development. J Exp Med 204:1037–1047

    Article  PubMed  CAS  Google Scholar 

  25. Pedroza-Gonzalez A, Xu K, Wu TC, Aspord C, Tindle S, Marches F, Gallegos M, Burton EC, Savino D, Hori T, Tanaka Y, Zurawski S, Zurawski G, Bover L, Liu YJ, Banchereau J, Palucka AK (2011) Thymic stromal lymphopoietin fosters human breast tumor growth by promoting type 2 inflammation. J Exp Med 208:479–490

    Article  PubMed  CAS  Google Scholar 

  26. Caras I, Grigorescu A, Stavaru C, Radu DL, Mogos I, Szegli G, Salageanu A (2004) Evidence for immune defects in breast and lung cancer patients. Cancer Immunol Immunother 53:1146–1152

    Article  PubMed  CAS  Google Scholar 

  27. Gabitass RF, Annels NE, Stocken DD, Pandha HA, Middleton GW (2011) Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13. Cancer Immunol Immunother 60:1419–1430

    Article  PubMed  CAS  Google Scholar 

  28. Akkoc T, de Koning PJ, Ruckert B, Barlan I, Akdis M, Akdis CA (2008) Increased activation-induced cell death of high IFN-gamma-producing T(H)1 cells as a mechanism of T(H)2 predominance in atopic diseases. J Allergy Clin Immunol 121(652–658):e651

    Google Scholar 

  29. Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495–516

    Article  PubMed  CAS  Google Scholar 

  30. Ilan N, Mohsenin A, Cheung L, Madri JA (2001) PECAM-1 shedding during apoptosis generates a membrane-anchored truncated molecule with unique signaling characteristics. FASEB J 15:362–372

    Article  PubMed  CAS  Google Scholar 

  31. Miyake Y, Asano K, Kaise H, Uemura M, Nakayama M, Tanaka M (2007) Critical role of macrophages in the marginal zone in the suppression of immune responses to apoptotic cell-associated antigens. J Clin Invest 117:2268–2278

    Article  PubMed  CAS  Google Scholar 

  32. Yoon TJ, Kim JY, Kim H, Hong C, Lee H, Lee CK, Lee KH, Hong S, Park SH (2008) Anti-tumor immunostimulatory effect of heat-killed tumor cells. Exp Mol Med 40:130–144

    Article  PubMed  CAS  Google Scholar 

  33. Kaczmarek A, Vandenabeele P, Krysko DV (2013) Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity 38:209–223

    Article  PubMed  CAS  Google Scholar 

  34. Tsuji T, Matsuzaki J, Ritter E, Miliotto A, Ritter G, Odunsi K, Old LJ, Gnjatic S (2011) Split T cell tolerance against a self/tumor antigen: spontaneous CD4 + but not CD8 + T cell responses against p53 in cancer patients and healthy donors. PLoS ONE 6:e23651

    Article  PubMed  CAS  Google Scholar 

  35. Alvarez-Rodriguez L, Lopez-Hoyos M, Munoz-Cacho P, Martinez-Taboada VM (2012) Aging is associated with circulating cytokine dysregulation. Cell Immunol 273:124–132

    Article  PubMed  CAS  Google Scholar 

  36. Sakata-Kaneko S, Wakatsuki Y, Matsunaga Y, Usui T, Kita T (2000) Altered Th1/Th2 commitment in human CD4 + T cells with ageing. Clin Exp Immunol 120:267–273

    Article  PubMed  CAS  Google Scholar 

  37. Strissel KJ, DeFuria J, Shaul ME, Bennett G, Greenberg AS, Obin MS (2010) T-cell recruitment and Th1 polarization in adipose tissue during diet-induced obesity in C57BL/6 mice. Obesity (Silver Spring) 18:1918–1925

    Article  CAS  Google Scholar 

  38. Marques BG, Hausman DB, Martin RJ (1998) Association of fat cell size and paracrine growth factors in development of hyperplastic obesity. Am J Physiol 275:R1898–R1908

    PubMed  CAS  Google Scholar 

  39. Hausman DB, DiGirolamo M, Bartness TJ, Hausman GJ, Martin RJ (2001) The biology of white adipocyte proliferation. Obes Rev 2:239–254

    Article  PubMed  CAS  Google Scholar 

  40. van der Burg SH, Menon AG, Redeker A, Bonnet MC, Drijfhout JW, Tollenaar RA, van de Velde CJ, Moingeon P, Kuppen PJ, Offringa R, Melief CJ (2002) Induction of p53-specific immune responses in colorectal cancer patients receiving a recombinant ALVAC-p53 candidate vaccine. Clin Cancer Res 8:1019–1027

    PubMed  Google Scholar 

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Acknowledgments

This work was supported by a grant from the Ovarian Cancer Research Fund, 17624550-36370-A, and a Department of Defense Postdoctoral Fellowship, W81XWH-10-1-0700. MLD is supported by the Athena Distinguished Professorship of Breast Cancer Research.

Conflict of Interest

MLD discloses funding received from Seattle Genetics, stock ownership in VentiRx and Epigenomics AG, and a consultant/advisory role at VentiRx and EMD Serono. All other authors disclose no conflict of interest.

Ethical Standards

All authors declare that the experiments comply with current U.S. laws.

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Authors and Affiliations

  1. Tumor Vaccine Group, Center for Translational Medicine in Women’s Health, University of Washington, 850 Republican Street, Seattle, WA, 98109, USA

    Denise L. Cecil, Ekram Gad, Jennifer S. Childs, Doreen M. Higgins & Mary L. Disis

  2. Division of Oncology/Hematology, Department of Internal Medicine, Korea University, Seoul, Korea

    Kyong Hwa Park

  3. Department of Medicine, University of Washington, Seattle, WA, USA

    Stephen R. Plymate

  4. GRECC and Research Service, Department of Veterans Affairs Medical Center, Seattle, WA, USA

    Stephen R. Plymate

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  1. Denise L. Cecil
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  2. Kyong Hwa Park
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Correspondence to Denise L. Cecil.

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Cecil, D.L., Park, K.H., Gad, E. et al. T-helper I immunity, specific for the breast cancer antigen insulin-like growth factor-I receptor (IGF-IR), is associated with increased adiposity. Breast Cancer Res Treat 139, 657–665 (2013). https://doi.org/10.1007/s10549-013-2577-z

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