Efficient cross-priming of tumor antigen-specific T cells by dendritic cells sensitized with diverse anti-MICA opsonized tumor cells

Abstract

D endritic cells (DCs) have a central role in the initiation and control of T cell-mediated immunity. Immature DCs residing in tissues endocytose soluble antigens, microbes, or apoptotic cells, and receive microbial or inflammatory maturation cues depending on the type of pathogen and the nature and extent of tissue damage (1-3). Maturing DCs migrate to lymph nodes via afferent lymphatics where they complete their maturation and present peptides derived from protein degradation on MHC class I and class II molecules to CD8 and CD4 T cells, respectively (2). The type and composition of maturation signals received by DCs determine whether they induce productive T cell responses or tolerance (4, 5).Because of their potent immunostimulatory capacity, there is much interest in employing DCs as tumor vaccines to induce effector and long-term memory CD4 and CD8 T cells with broad tumor antigen (TA) specificities (6-8). Early-stage trials using ex vivo TA-loaded and matured monocyte-or CD34 ϩ progenitorderived DCs have provided some evidence for clinically beneficial immunostimulatory effects (9, 10). However, many variables remain to be explored, including antigen sources and modes of DC antigen-loading. Most commonly, DCs are pulsed with synthetic TA-derived MHC-binding peptides (11,12). This approach is constrained by limited knowledge of TA, their natural and immunoselected variation within and among tumors, and by the MHC allele-specific restrictions of peptide-binding, thus producing narrow repertoires of antigen-specific T cells. Other methods include transfection of DCs with tumor-derived RNA, the use of viral vectors for expression of TA, and facilitating DC uptake of tumorderived exosomes, apoptotic tumor cells, or recombinant proteins for antigen processing and presentation (13)(14)(15)(16)(17)(18)(19). Moreover, DC expression of Ig Fc receptors (Fc␥R) can be exploited for targeting immune complexes and antibody-coated tumor cells to DCs (20,21). Exposure of DCs to anti-syndecan mAb-opsonized myeloma cells promotes efficient in vitro cross-priming of cytotoxic T lymphocytes, yielding results that are superior to cross-presentation of TA from apoptotic tumor cells (22).This immunization mode is appealing because it may operate in vivo and contribute to the beneficial effects of some antibody-based cancer therapies (23,24). Hence, antibody targeting of surface molecules that are absent from most cell types and tissues but are frequently tumor-associated could be a viable approach to inducing tumor immunity. Suitable candidate molecules are MHC class I chain-related proteins A (MICA) and B (MICB), which are distantly related to MHC class I and function as ligands of the NKG2D receptor on natural killer cells and T cell subsets (25,26). In healthy individuals, the tissue distribution of MIC is restricted to variable areas of gastrointestinal epithelium (25, 27). However, MICs are abundantly expressed in many lung, breast, kidney, ovarian, prostate, gastric, and colon carcinomas, and melanomas, as well as in certai...

Engineered antibody Fc variants with enhanced effector function

“…Additionally, Fc␥R-mediated phagocytosis and endocytosis are mechanisms of antigen uptake, potentially leading to antigen presentation and adaptive immunity (25). Fc␥R-and Ab-mediated dendritic cell maturation, antigen presentation, and antitumor T cell immunity have been demonstrated in mice (30)(31)(32) and by human cells in vitro (33)(34)(35). Nonetheless, the role of adaptive immunity in mAb therapy remains unclear.…”

Recruiting dendritic cells to improve antibody therapy of cancer

“…The finding of enhanced generation of T cell immunity after uptake of opsonized tumor in this and other studies suggests a role for DCs in recruitment of T cell immunity via antitumor mAbs (3,12,14). Such responses would be desirable, because they provide a mechanism for long-term protection and immunologic memory.…”

Therapy-induced antibodies to MHC class I chain-related protein A antagonize immune suppression and stimulate antitumor cytotoxicity

“…Whereas sMICA inhibits CD8 ϩ T lymphocyte cytotoxicity through down-regulation of NKG2D (10), anti-MICA antibodies promote dendritic cellmediated cross-presentation of tumor cells (12). To explore these mechanisms in MEL15, we purified CD8 ϩ T cells from healthy donors, incubated them for 48 h in various sera, and then performed flow cytometry (Fig.…”