Skip to main content

Advertisement

SpringerLink
Log in

Sequential immune monitoring in patients with melanoma and renal cell carcinoma treated with high-dose interleukin-2: immune patterns and correlation with outcome

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Interleukin-2 (IL-2) therapy leads to clinically relevant responses in 10–16 % of patients with metastatic melanoma (MMEL) or 10–30 % of patients with metastatic renal cell carcinoma (MRCC). To date, no biomarkers have been validated to identify patients who are likely to respond. We hypothesized that changes in T cell subset distribution in patients undergoing IL-2 therapy may correlate with treatment outcomes. Immune profiles of 64 patients (27-MMEL, 37-MRCC) were evaluated using flow cytometry at baseline, during (≥three doses) and at the end of treatment cycle (30 ± 6 h after last dose), through two courses of IL-2 therapy. Changes in distribution and phenotype of circulating CD4 and CD8 lymphocyte subsets were compared (1) based on cancer types and (2) intra-patient during the course of the IL-2 therapy. Exploratory analysis of immunologic profiles was also performed based on treatment outcome. Independent of cancer type, IL-2 led to a transient decrease of circulating effector lymphocytes, while regulatory T cells gradually increased. Interleukin-2 differentially affected a subset of CD8 T cell expressing Foxp3, depending on malignancy type. In MMEL patients, IL-2 gradually expanded circulating CD8 Foxp3+ cells; in MRCC patients, IL-2 transiently increased expression of CD103 and CCR4 homing markers. Monitoring of adaptive immune variables early on and during the course of IL-2 therapy revealed transient alterations in immune profiles, specific to MMEL and MRCC patients, related to immune balance (and ultimately response to IL-2 therapy) or T cell egress from the circulation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

CR:

Complete response

Foxp3:

Forkhead box P3

GEE:

Generalized estimating equations

IL-2:

Interleukin-2

LDH:

Lactate dehydrogenase

MIATA:

Minimal information about T cell assay

MMEL:

Metastatic melanoma

MR:

Minor response

MRCC:

Metastatic renal cell carcinoma

PBMC:

Peripheral mononuclear cells

PD:

Progressive disease

PR:

Partial response

RECIST:

Response evaluation criteria in solid tumor

RT:

Room temperature

SD:

Stable disease

Treg:

Regulatory T cell

ULN:

Upper limit of normal

References

  1. Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L, Rosenberg SA (1999) High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17(7):2105–2116

    CAS  PubMed  Google Scholar 

  2. Riker AI, Radfar S, Liu S, Wang Y, Khong HT (2007) Immunotherapy of melanoma: a critical review of current concepts and future strategies. Expert Opin Biol Ther 7(3):345–358. doi:10.1517/14712598.7.3.345

    Article  CAS  PubMed  Google Scholar 

  3. Rosenberg SA, Lotze MT, Muul LM, Chang AE, Avis FP, Leitman S, Linehan WM, Robertson CN, Lee RE, Rubin JT et al (1987) A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 316(15):889–897. doi:10.1056/NEJM198704093161501

    Article  CAS  PubMed  Google Scholar 

  4. Sun M, Lughezzani G, Perrotte P, Karakiewicz PI (2010) Treatment of metastatic renal cell carcinoma. Nat Rev Urol 7(6):327–338. doi:10.1038/nrurol.2010.57

    Article  CAS  PubMed  Google Scholar 

  5. Ma A, Koka R, Burkett P (2006) Diverse functions of IL-2, IL-15, and IL-7 in lymphoid homeostasis. Annu Rev Immunol 24:657–679. doi:10.1146/annurev.immunol.24.021605.090727

    Article  CAS  PubMed  Google Scholar 

  6. Boyman O, Sprent J (2012) The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol 12(3):180–190. doi:10.1038/nri3156

    CAS  PubMed  Google Scholar 

  7. Foureau DM, McKillop IH, Jones CP, Amin A, White RL, Salo JC (2011) Skin tumor responsiveness to interleukin-2 treatment and CD8 Foxp3+ T cell expansion in an immunocompetent mouse model. Cancer Immunol Immunother 60(9):1347–1356. doi:10.1007/s00262-011-1035-1

    Article  CAS  PubMed  Google Scholar 

  8. Garibal J, Laforge M, Silvestre R, Mouhamad S, Campillo-Gimenez L, Levy Y, Estaquier J (2012) IL-2 immunotherapy in chronically SIV-infected Rhesus macaques. Virol J 9:220. doi:10.1186/1743-422X-9-220

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Sparano JA, Fisher RI, Sunderland M, Margolin K, Ernest ML, Sznol M, Atkins MB, Dutcher JP, Micetich KC, Weiss GR et al (1993) Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma. J Clin Oncol 11(10):1969–1977

    CAS  PubMed  Google Scholar 

  10. Curran SD, Muellner AU, Schwartz LH (2006) Imaging response assessment in oncology. Cancer Imaging 6:S126–S130. doi:10.1102/1470-7330.2006.9039

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Kirkwood JM, Tarhini AA (2009) Biomarkers of therapeutic response in melanoma and renal cell carcinoma: potential inroads to improved immunotherapy. J Clin Oncol 27(16):2583–2585. doi:10.1200/JCO.2008.21.1540

    Article  CAS  PubMed  Google Scholar 

  12. McDermott DF, Regan MM, Atkins MB (2006) Interleukin-2 therapy of metastatic renal cell carcinoma: update of phase III trials. Clin Genitourin Cancer 5(2):114–119. doi:10.3816/CGC.2006.n.027

    Article  CAS  PubMed  Google Scholar 

  13. Petrella T, Quirt I, Verma S, Haynes AE, Charette M, Bak K (2007) Single-agent interleukin-2 in the treatment of metastatic melanoma. Curr Oncol 14(1):21–26

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. White RL Jr, Amin A (2011) Cancer immunotherapy. Surg Oncol Clin N Am 20(3):531–554, ix. doi:10.1016/j.soc.2011.01.010

  15. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216

    Article  CAS  PubMed  Google Scholar 

  16. Janetzki S, Britten CM, Kalos M, Levitsky HI, Maecker HT, Melief CJ, Old LJ, Romero P, Hoos A, Davis MM (2009) “MIATA”-minimal information about T cell assays. Immunity 31(4):527–528. doi:10.1016/j.immuni.2009.09.007

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Kmieciak M, Gowda M, Graham L, Godder K, Bear HD, Marincola FM, Manjili MH (2009) Human T cells express CD25 and Foxp3 upon activation and exhibit effector/memory phenotypes without any regulatory/suppressor function. J Transl Med 7:89. doi:10.1186/1479-5876-7-89

    Article  PubMed Central  PubMed  Google Scholar 

  18. Khattak M, Fisher R, Turajlic S, Larkin J (2013) Targeted therapy and immunotherapy in advanced melanoma: an evolving paradigm. Ther Adv Med Oncol 5(2):105–118. doi:10.1177/1758834012466280

    Article  PubMed Central  PubMed  Google Scholar 

  19. Friedlander P, Hodi FS (2010) Advances in targeted therapy for melanoma. Clin Adv Hematol Oncol 8(9):619–627

    PubMed  Google Scholar 

  20. Eisen T, Sternberg CN, Robert C, Mulders P, Pyle L, Zbinden S, Izzedine H, Escudier B (2012) Targeted therapies for renal cell carcinoma: review of adverse event management strategies. J Natl Cancer Inst 104(2):93–113. doi:10.1093/jnci/djr511

    Article  CAS  PubMed  Google Scholar 

  21. Cunningham-Rundles C, Bodian C, Ochs HD, Martin S, Reiter-Wong M, Zhuo Z (2001) Long-term low-dose IL-2 enhances immune function in common variable immunodeficiency. Clin Immunol 100(2):181–190. doi:10.1006/clim.2001.5052

    Article  CAS  PubMed  Google Scholar 

  22. Smith-Garvin JE, Koretzky GA, Jordan MS (2009) T cell activation. Annu Rev Immunol 27:591–619. doi:10.1146/annurev.immunol.021908.132706

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY (2005) A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 6(11):1142–1151. doi:10.1038/ni1263

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was funded in part by a seed grant from the Carolinas Healthcare Foundation, the Purple Promise Foundation to end Melanoma and the Freedland Foundation. We thank Dr. Carol Farhangfar for comments on the manuscript, Dr. H James Norton for helping with statistical analysis, Joey Armstrong and Kendall Carpenter for compiling clinical data and Patricia Hevey for semantic and syntactic corrections.

Conflict of interest

Drs. Amin and White are members of Prometheus speaker’s bureau. All other authors have no commercial or consultancy conflict of interest.

Author information

Authors and Affiliations

  1. Department of General Surgery, Carolinas Healthcare System, Charlotte, NC, 28203, USA

    David M. Foureau, Richard L. White, Chase P. Jones, Terry Sarantou, Iain H. McKillop & Jonathan C. Salo

  2. Levine Cancer Institute, Carolinas Healthcare System, Charlotte, NC, 28203, USA

    Asim Amin, Richard L. White, Terry Sarantou & Jonathan C. Salo

  3. Dickson Advanced Analytic Group, Carolinas Healthcare System, Charlotte, NC, 28203, USA

    William Anderson

Authors
  1. David M. Foureau
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Asim Amin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard L. White
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. William Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chase P. Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Terry Sarantou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Iain H. McKillop
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jonathan C. Salo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David M. Foureau.

Additional information

The authors of this paper report on their T cell assays transparently and comprehensively as per field-wide consensus, allowing the community a full understanding and interpretation of presented data as well as a comparison of data between groups. The electronic supplementary materials of this publication include a MIATA checklist. For more details, see http://miataproject.org/.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 417 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Foureau, D.M., Amin, A., White, R.L. et al. Sequential immune monitoring in patients with melanoma and renal cell carcinoma treated with high-dose interleukin-2: immune patterns and correlation with outcome. Cancer Immunol Immunother 63, 1329–1340 (2014). https://doi.org/10.1007/s00262-014-1605-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-014-1605-0

Keywords

Search

Navigation