Modulation of T-Cell Activation by Malignant Melanoma Initiating Cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2010-01, Vol.70 (2), p.697-708
• Main Authors: SCHATTON, Tobias, SCHÜTTE, Ute, FRANK, Markus H, FRANK, Natasha Y, QIAN ZHAN, HOERNING, André, ROBLES, Susanne C, JUN ZHOU, HODI, F. Stephen, SPAGNOLI, Giulio C, MURPHY, George F
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Neoplasm - immunology; Antineoplastic agents; ATP-Binding Cassette, Sub-Family B, Member 1 - biosynthesis; ATP-Binding Cassette, Sub-Family B, Member 1 - immunology; Biological and medical sciences; Dermatology; Humans; Leukocytes, Mononuclear - immunology; Lymphocyte Activation; Medical sciences; Melanoma - immunology; Melanoma - pathology; Mice; Mice, Inbred NOD; Mice, SCID; Neoplastic Stem Cells - immunology; Neoplastic Stem Cells - pathology; Pharmacology. Drug treatments; T-Lymphocytes, Regulatory - immunology; Tumors; Tumors of the skin and soft tissue. Premalignant lesions
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-09-1592

Highly immunogenic cancers such as malignant melanoma are capable of inexorable tumor growth despite the presence of antitumor immunity. Thus, only a restricted minority of tumorigenic malignant cells may possess the phenotypic and functional characteristics needed to modulate tumor-directed immune activation. Here we provide evidence supporting this hypothesis. Tumorigenic ABCB5(+) malignant melanoma initiating cells (MMICs) possessed the capacity to preferentially inhibit IL-2-dependent T-cell activation and to support, in a B7.2-dependent manner, induction of CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs). Compared with melanoma bulk cell populations, ABCB5(+) MMICs displayed lower levels of MHC class I, aberrant positivity for MHC class II, and lower expression levels of the melanoma-associated antigens MART-1, ML-IAP, NY-ESO-1, and MAGE-A. Additionally, these tumorigenic ABCB5(+) subpopulations preferentially expressed the costimulatory molecules B7.2 and PD-1, both in established melanoma xenografts and in clinical tumor specimens. In immune activation assays, MMICs inhibited mitogen-dependent human peripheral blood mononuclear cell (PBMC) proliferation and IL-2 production more efficiently than ABCB5(-) melanoma cell populations. Moreover, coculture with ABCB5(+) MMICs increased the abundance of Tregs, in a B7.2 signaling-dependent manner, along with IL-10 production by mitogen-activated PBMCs. Consistent with these findings, MMICs also preferentially inhibited IL-2 production and induced IL-10 secretion by cocultured patient-derived, syngeneic PBMCs. Our findings identify novel T-cell modulatory functions of ABCB5(+) melanoma subpopulations and suggest specific roles for these MMICs in the evasion of antitumor immunity and in cancer immunotherapeutic resistance.