CD69 on CD56+ NK cells and response to chemoimmunotherapy in metastatic melanoma

• Published in: European journal of clinical investigation Vol. 37; no. 11; pp. 887 - 896
• Main Authors: KONJEVIC, G, JOVIC, V, VULETIC, A, RADULOVIC, S, JELIC, S, SPUZIC, I
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-11-2007; Blackwell
• Subjects: 13-cis retinoic acid; Adult; Aged; Antigens, CD - immunology; Antigens, CD - metabolism; Antigens, Differentiation, T-Lymphocyte - immunology; Antigens, Differentiation, T-Lymphocyte - metabolism; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Case-Control Studies; CD56 Antigen - immunology; CD56 Antigen - metabolism; CD69; dacarbazine; Dacarbazine - administration & dosage; Dermatology; Female; General aspects; Humans; Immunotherapy - methods; Interferon Regulatory Factor-1 - immunology; interferon α; Interferon-alpha - administration & dosage; Killer Cells, Natural - immunology; Lectins, C-Type; Male; Medical sciences; melanoma; Melanoma - immunology; Melanoma - therapy; Middle Aged; NK cells; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction - methods; Skin Neoplasms - immunology; Skin Neoplasms - therapy; Tretinoin - administration & dosage; Tumors of the skin and soft tissue. Premalignant lesions; Antineoplastic agent; NK cells; Alpha interferon; Retinoid; melanoma; Malignant tumor; Metastasis; Natural killer cell; Medicine; Dacarbazine; Alkylating agent; Malignant melanoma; Advanced stage; interferon α; Isotretinoin; Metastatic; 13-cis retinoic acid; CD69
• ISSN: 0014-2972; 1365-2362
• DOI: 10.1111/j.1365-2362.2007.01873.x

Background  The few chemoimmunotherapy trials that together with dacarbazine (DTIC) and interferon‐α 2a (IFNα), include retinoic acid (RA), did not include detailed immunological evaluation of functional and phenotypic natural killer (NK) cell characteristics, and have shown contradictory clinical results.
Materials and methods  Malignant melanoma (MM) patients undergoing phase II‐randomized chemoimmunotherapy trials were treated with DTIC, IFNα (Hoffmann‐La Roche) (group A, n = 31), and with DTIC, IFNα and 13‐cis‐RA (Isotretinoin, Hoffmann‐La Roche, Basel, Switzerland) (group B, n = 29). Patients and 42 healthy controls were evaluated by FACS flow analyses for CD3/CD56/CD69 positive cells, NK cytotoxicity in fresh peripheral blood lymphocytes (PBL) and for interferon regulatory factor‐1 mRNA expression by reverse transcriptase polymerase chain reaction in treated PBL.
Results  The addition of RA to a DTIC‐IFN regime did not bring any therapeutical benefit in terms of response or survival. Immunological follow‐up on days 1, 6 and 27 of each therapy cycle shows a significant increase in NK cell activity in both groups, only on day 6 of the first cycle, while CD69+CD56+ expression increased significantly on day 6 of each therapy cycle, in both groups. Evaluation of the dynamics of expression of IRF‐1 of in vitro treated PBL, shows its strong and prompt up‐regulation by IFNα and synergistic effect of IFNα and RA combination.
Conclusion  The dynamics of the increase in CD69 early activation antigen expression on CD56+ NK cells is systematic and serial with the increase being significantly higher on day six of the first cycle in group B patients with clinical response, compared to those without, indicating possible predictive value of CD69 expression for clinical response to chemoimmunotherapy.