Three Dimensional Niches That Regulate Immune Responses In Situ

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As a promising alternative to cell-based approaches (e.g., DC-based vaccines and adoptive T cell transfer) for cancer immunotherapy, biomaterials may be fashioned into three-dimensional matrices that regulate immune cell trafficking and activation in situ (Huebsch and Mooney 2009). Immune mechanisms have evolved to recognize and defend against pathogenic infection, and now infection-mimicking microenvironments may be developed using synthetic ECMs and immune cell niches aimed at promoting effective immune responses to cancer antigens. Three-dimensional biomaterial constructs may be designed to support DC and T cell transplantation or recruitment for extended periods while providing a distinct activating niche, via the controlled presentation of antigens and adjuvants while DCs reside within the matrix.

Vaccine nodes were developed by utilizing injectable alginate hydrogels that crosslinked in vivo into a supporting matrix containing activated DCs. These transplanted DCs produced cytokines that recruited both host DCs and T cells to the injection site, and the vaccine site subsequently transformed into a potent T cell effector site that could be useful for local tumor immunotherapy (Hori et al. 2008). Moreover, these three-dimensional, DC niches were able to maintain cell viability, and DC and T cell in situ recruitment for over a week (Hori et al. 2008). Similar alginate hydrogel systems were also used to control the release of immunocytokines (IL-15 superagonist) and danger signaling to recruit and activate cytotoxic T cells, and peritumoral injections of these systems significantly enhanced the survival of melanoma-bearing mice (Hori et al. 2009).

Fig.2 (continued) embedded with programming factors (tumor antigens and adjuvants) to activate resident DCs (recruited or transplanted) in situ into an antitumor state with upregulated antigen expression and costimulatory molecules (for T cell priming). These activated DCs may be deployed and home to lymphoid tissue to stimulate antigen-specific CTL responses. These systems may continuously produce activated DCs in situ for sustain periods, prolonging the induction of antitumor responses. Alternative approaches include three-dimensional biomaterials developed to deliver tumor specific T cells or to act as CTL effector sites for local tumor therapy

A recent series of studies describe the development of implantable, and macro-porous polymer matrices (PLG; ^85% of the volume is pores) that mimic infectious microenvironments to regulate DC and T cell trafficking and activation in situ (Ali et al. 2009a). Following subcutaneous implantation, GM-CSF was released from these PLG matrices into the surrounding tissue, to recruit significant numbers of host DCs (~3 x 106 cells) (Ali et al. 2009b). CpG-rich oligonucleotides were also immobilized on the matrices as danger signals, and antigen (tumor lysates within the PLG) was released to matrix resident DCs to program DC development and maturation (Ali et al. 2009b). This coordination of DC migration and activation (as DCs reside within the matrix) induced potent, prolonged, and specific cytotoxic, T cell mediated immunity (both local and systemically) that completely eradicated large B16 melanoma tumors in mice (>25 mm2 at the time of vaccination; 55% long-term therapeutic cure rate) (Ali et al. 2009a, b).

Interestingly, these systems can also be utilized to determine the cellular and molecular signatures of effective therapeutic immune responses to solid tumors; as a critical number and pattern of DC subset generation at the vaccine site, including plasmacytoid DCs (pDCs) and CD8+ DCs (not commonly included in ex vivo DC vaccines), strongly correlated with vaccine efficacy (Ali et al. 2009b). Moreover, the aforementioned immune niches begin as vaccine nodes and translate into the formation of distinct T cell effector sites, which can be monitored to elucidate the cellular and molecular interactions that govern antitumor activities in the therapeutic setting (Hori et al. 2008; Ali et al. 2009b; Hori et al. 2009). These insights into vaccine and effector immunobiology enabled by this biomaterial approach may provide important design criteria (e.g., CD8+ DCs and pDCs as cellular targets) for future cancer immunotherapy.

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