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

Howard L Kaufman⁵  Andrew Zloza⁵  David Masopust¹  Jason M Schenkel¹  Jai S Rudra²  Joshua D Snook²  Carl E Ruby³  Arman Nabatiyan⁶  Joseph L Poshepny⁴  Graham E Hill⁴  Alisa Grin⁴  Vidyaratna A Fleetwood³  Hubert Dolubizno⁴  Janet P Zayas⁴  Jevgenijs Lusciks⁴  Erica J Huelsmann⁴  Tasha Hughes³  Joseph R Broucek³  Frederick J Kohlhapp⁴ 

[1] Department of Microbiology and Center for Immunology, University of Minnesota Medical School, Minneapolis 55455, MN, USA;Department of Pharmacology & Toxicology and Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston 77555, TX, USA;Department of General Surgery, Rush University Medical Center, Chicago 60612, IL, USA;Department of Immunology/Microbiology, Rush University Medical Center, Chicago 60612, IL, USA;Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick 08903, NJ, USA;Department of Internal Medicine, Rush University Medical Center, Chicago 60612, IL, USA

关键词: CD8+ T cells;    NK cells;    CTLA-4;    Interleukin-2;    Immunotherapy;   

Others  :  1205871
DOI  :  10.1186/s40425-015-0063-3

 received in 2015-03-09, accepted in 2015-04-17,  发布年份 2015

【 摘 要 】

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 (100 μg/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.

【 授权许可】

   
2015 Kohlhapp et al.; licensee BioMed Central.

【 图 表 】

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