Schematic model of candidate mechanisms underlying malignant melanoma initiating cell (MMIC)-driven tumor immune evasion. Many of the processes underlying tolerance induction by physiologic stem cells parallel mechanisms of immune evasion relevant to neoplastic development, disease progression, and therapy-resistance of immunogenic cancers, including human malignant melanoma. It is possible that the CSC component within a tumor may possess a preferential capacity to mitigate the antitumor immune response, and that such a potential function of ABCB5⁺ MMIC might contribute to melanomagenesis. MMIC could evade rejection by tumor antigen–specific CD8⁺ immune effector populations through absent or reduced expression of tumor-associated antigens, such as MART-1, or decreased MHC class I molecule expression. Alternatively, T cell ignorance of MMIC may also result from spatial separation. Direct deletion of immune effector cells through induction of apoptotic cell death (e.g., through expression of apoptosis-inducing ligands, such as Fas-L) might represent an additional mechanism of MMIC-driven tumor escape from immune destruction. ABCB5⁺ MMIC could possibly also tolerize tumor-reactive T cells via direct secretion of immunosuppressive factors, including TGF-β or IL-10. Cross-presentation of tumor-associated or MMIC-specific antigens by APC incapable of providing adequate costimulation might likewise induce tumor tolerance by rendering melanoma-reactive T cells anergic. Furthermore, ABCB5⁺ MMIC could potentially also tolerize melanoma-specific T cells by delivering a negative costimulatory signal (e.g., via PD/PD-L1 or B7/CTLA-4 pathways) at the time of alloantigen recognition. Finally, MMIC might actively induce or recruit regulatory T cells to disrupt the antimelanoma immune response.

Schematic overview of costimulatory receptors and their ligands. Illustrated are costimulatory ligands and their respective receptors, which can deliver signals that function to either activate (+) or downregulate (−) immune responses in tandem with alloantigen-specific T cell receptor engagement with the MHC/peptide complex. Costimulatory molecules can be grouped broadly into two distinct superfamilies based on structural homology: the CD28:B7 superfamily, which includes CD28 and CTLA-4, and the TNF:TNF-R superfamily, in which the CD40-CD40L pathway is pre-eminent. Costimulatory molecules were originally described in immune cells. It is increasingly recognized, however, that costimulatory signaling can also occur in nonlymphoid cells, including cancer cells.

Representative dual-color flow cytometry analysis of human A375 melanoma cells costained for ABCB5 (APC, FL4 fluorescence) and the melanoma antigen recognized by T cells-1 (MART-1) (FITC, FL1 fluorescence). ABCB5⁺ cells co-expressing MART-1 are found in the top right quadrant of the left fluorescence plot. The right fluorescence plot depicts isotype control mAb-stained melanoma cells.

The “two-signal” paradigm of antigen-dependent T cell activation. According to the “two-signal” paradigm, antigen-dependent T cell activation requires two distinct but synergistic signals. (A) On antigen encounter, naïve T cells receive signal 1 through T cell receptor engagement with the MHC/antigenic peptide complex expressed on an APC, and signal 2 through ligation of a positive costimulatory receptor/ligand pair leading to full activation. Positive costimulation leads to T cell activation, proliferation, and cytokine production, drives naïve T helper cells into differentiation, and may inhibit T cell anergy and apoptosis. (B) By contrast, negative T cell costimulatory signals function to downregulate immune responses. T cell receptor engagement coincident with negative costimulation inhibits T cell proliferation and cytokine secretion, induces T cell anergy and apoptosis, and may control the suppressive function of regulatory T cells. Signal 1–associated molecules (MHC class I and II) and signal 2 pathway members (positve and negative costimulatory molecules) are regulated not only on T cells and APC; expression can also be observed on other lymphocyte compartments as well as in nonlymphoid cells, including cancer cells.