NK cells and CD8+ T cells cooperate to improve therapeutic responses in melanoma treated with interleukin-2 (IL-2) and CTLA-4 blockade

Frederick J. Kohlhapp, Joseph R. Broucek, Tasha Hughes, Erica J. Huelsmann, Jevgenijs Lusciks, Janet P. Zayas, Hubert Dolubizno, Vidyaratna A. Fleetwood, Alisa Grin, Graham E. Hill, Joseph L. Poshepny, Arman Nabatiyan, Carl E. Ruby, Joshua D. Snook, Jai S. Rudra, Jason M. Schenkel, David Masopust, Andrew Zloza, Howard L. Kaufman

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Background: Melanoma is one of the few types of cancer with an increasing annual incidence. While a number of immunotherapies for melanoma have been associated with significant clinical benefit, including high-dose IL-2 and cytotoxic T lymphocyte antigen 4 (CTLA-4) blockade, clinical response to either of these single agents has been limited to 11-20% of treated patients. Therefore, in this study, we sought to test the hypothesis that the combination of IL-2 and CTLA-4 blockade could mediate a more profound therapeutic response. Methods: Here, B6 mice were challenged with poorly immunogenic B16 melanoma on day 0, and treated with CTLA-4 blocking antibody (100μg/mouse) on days 3, 6, and 9, and IL-2 (100,000 units) twice daily on days 4-8, or both. Results: A highly significant synergistic effect that delayed tumor growth and prolonged survival was demonstrated with the combination immunotherapy compared to either monotherapy alone. The therapeutic effect of combination immunotherapy was dependent on both CD8+ T and NK cells and co-depletion of these subsets (but not either one alone) abrogated the therapeutic effect. CTLA-4 blockade increased immune cell infiltration (including CD8+ T cells and NK cells) in the tumor and IL-2 reduced the proportion of highly differentiated/exhausted tumor-infiltrating NK cells. Conclusions: These results have implications for the design of clinical trials in patients with metastatic melanoma and provide new insights into how the immune system may be mediating anti-tumor activity with combination IL-2 and CTLA-4 blockade in melanoma.

Original languageEnglish (US)
Article number18
JournalJournal for ImmunoTherapy of Cancer
Volume3
Issue number1
DOIs
StatePublished - May 19 2015

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CTLA-4 Antigen
Natural Killer Cells
Interleukin-2
Melanoma
T-Lymphocytes
Immunotherapy
Therapeutic Uses
Neoplasms
Therapeutics
Experimental Melanomas
Blocking Antibodies
Immune System
Clinical Trials
Survival
Incidence
Growth

Keywords

  • CD8+ T cells
  • CTLA-4
  • Immunotherapy
  • Interleukin-2
  • NK cells

ASJC Scopus subject areas

  • Oncology
  • Immunology and Allergy
  • Cancer Research
  • Molecular Medicine
  • Pharmacology
  • Immunology

Cite this

NK cells and CD8+ T cells cooperate to improve therapeutic responses in melanoma treated with interleukin-2 (IL-2) and CTLA-4 blockade. / Kohlhapp, Frederick J.; Broucek, Joseph R.; Hughes, Tasha; Huelsmann, Erica J.; Lusciks, Jevgenijs; Zayas, Janet P.; Dolubizno, Hubert; Fleetwood, Vidyaratna A.; Grin, Alisa; Hill, Graham E.; Poshepny, Joseph L.; Nabatiyan, Arman; Ruby, Carl E.; Snook, Joshua D.; Rudra, Jai S.; Schenkel, Jason M.; Masopust, David; Zloza, Andrew; Kaufman, Howard L.

In: Journal for ImmunoTherapy of Cancer, Vol. 3, No. 1, 18, 19.05.2015.

Research output: Contribution to journalArticle

Kohlhapp, FJ, Broucek, JR, Hughes, T, Huelsmann, EJ, Lusciks, J, Zayas, JP, Dolubizno, H, Fleetwood, VA, Grin, A, Hill, GE, Poshepny, JL, Nabatiyan, A, Ruby, CE, Snook, JD, Rudra, JS, Schenkel, JM, Masopust, D, Zloza, A & Kaufman, HL 2015, 'NK cells and CD8+ T cells cooperate to improve therapeutic responses in melanoma treated with interleukin-2 (IL-2) and CTLA-4 blockade', Journal for ImmunoTherapy of Cancer, vol. 3, no. 1, 18. https://doi.org/10.1186/s40425-015-0063-3
Kohlhapp, Frederick J. ; Broucek, Joseph R. ; Hughes, Tasha ; Huelsmann, Erica J. ; Lusciks, Jevgenijs ; Zayas, Janet P. ; Dolubizno, Hubert ; Fleetwood, Vidyaratna A. ; Grin, Alisa ; Hill, Graham E. ; Poshepny, Joseph L. ; Nabatiyan, Arman ; Ruby, Carl E. ; Snook, Joshua D. ; Rudra, Jai S. ; Schenkel, Jason M. ; Masopust, David ; Zloza, Andrew ; Kaufman, Howard L. / NK cells and CD8+ T cells cooperate to improve therapeutic responses in melanoma treated with interleukin-2 (IL-2) and CTLA-4 blockade. In: Journal for ImmunoTherapy of Cancer. 2015 ; Vol. 3, No. 1.
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T1 - NK cells and CD8+ T cells cooperate to improve therapeutic responses in melanoma treated with interleukin-2 (IL-2) and CTLA-4 blockade

AU - Kohlhapp, Frederick J.

AU - Broucek, Joseph R.

AU - Hughes, Tasha

AU - Huelsmann, Erica J.

AU - Lusciks, Jevgenijs

AU - Zayas, Janet P.

AU - Dolubizno, Hubert

AU - Fleetwood, Vidyaratna A.

AU - Grin, Alisa

AU - Hill, Graham E.

AU - Poshepny, Joseph L.

AU - Nabatiyan, Arman

AU - Ruby, Carl E.

AU - Snook, Joshua D.

AU - Rudra, Jai S.

AU - Schenkel, Jason M.

AU - Masopust, David

AU - Zloza, Andrew

AU - Kaufman, Howard L.

PY - 2015/5/19

Y1 - 2015/5/19

N2 - Background: Melanoma is one of the few types of cancer with an increasing annual incidence. While a number of immunotherapies for melanoma have been associated with significant clinical benefit, including high-dose IL-2 and cytotoxic T lymphocyte antigen 4 (CTLA-4) blockade, clinical response to either of these single agents has been limited to 11-20% of treated patients. Therefore, in this study, we sought to test the hypothesis that the combination of IL-2 and CTLA-4 blockade could mediate a more profound therapeutic response. Methods: Here, B6 mice were challenged with poorly immunogenic B16 melanoma on day 0, and treated with CTLA-4 blocking antibody (100μg/mouse) on days 3, 6, and 9, and IL-2 (100,000 units) twice daily on days 4-8, or both. Results: A highly significant synergistic effect that delayed tumor growth and prolonged survival was demonstrated with the combination immunotherapy compared to either monotherapy alone. The therapeutic effect of combination immunotherapy was dependent on both CD8+ T and NK cells and co-depletion of these subsets (but not either one alone) abrogated the therapeutic effect. CTLA-4 blockade increased immune cell infiltration (including CD8+ T cells and NK cells) in the tumor and IL-2 reduced the proportion of highly differentiated/exhausted tumor-infiltrating NK cells. Conclusions: These results have implications for the design of clinical trials in patients with metastatic melanoma and provide new insights into how the immune system may be mediating anti-tumor activity with combination IL-2 and CTLA-4 blockade in melanoma.

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