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

Autor: Kohlhapp FJ; Rutgers Cancer Institute of New Jersey, 195 Little Albany Street Room 2007, New Brunswick, NJ 08901 USA.; Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612 USA., Broucek JR; Department of General Surgery, Rush University Medical Center, Chicago, IL 60612 USA., Hughes T; Department of General Surgery, Rush University Medical Center, Chicago, IL 60612 USA., Huelsmann EJ; Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612 USA., Lusciks J; Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612 USA., Zayas JP; Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612 USA., Dolubizno H; Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612 USA., Fleetwood VA; Department of General Surgery, Rush University Medical Center, Chicago, IL 60612 USA., Grin A; Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612 USA., Hill GE; Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612 USA., Poshepny JL; Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612 USA., Nabatiyan A; Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612 USA.; Department of Internal Medicine, Rush University Medical Center, Chicago, IL 60612 USA., Ruby CE; Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612 USA.; Department of General Surgery, Rush University Medical Center, Chicago, IL 60612 USA., Snook JD; Department of Pharmacology & Toxicology and Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX 77555 USA., Rudra JS; Department of Pharmacology & Toxicology and Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX 77555 USA., Schenkel JM; Department of Microbiology and Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455 USA., Masopust D; Department of Microbiology and Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455 USA., Zloza A; Rutgers Cancer Institute of New Jersey, 195 Little Albany Street Room 2007, New Brunswick, NJ 08901 USA.; Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612 USA.; Department of Internal Medicine, Rush University Medical Center, Chicago, IL 60612 USA.; Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903 USA., Kaufman HL; Rutgers Cancer Institute of New Jersey, 195 Little Albany Street Room 2007, New Brunswick, NJ 08901 USA.; Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903 USA.
Jazyk: angličtina
Zdroj: Journal for immunotherapy of cancer [J Immunother Cancer] 2015 May 19; Vol. 3, pp. 18. Date of Electronic Publication: 2015 May 19 (Print Publication: 2015).
DOI: 10.1186/s40425-015-0063-3
Abstrakt: 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.
Databáze: MEDLINE
Externí odkaz: