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Donye Dominguez, Natalia Chernyak, Monica guan, Yushang Chou, Alan Long, Lei Qin, Lisa Cole, Jihae Ann, Siqi Chen, Jie Fan, Andrew Lee, Chad Mirkin, Bin Zhang, Robust antitumor effects of SNA-based T cell therapy, The Journal of Immunology, Volume 202, Issue 1_Supplement, May 2019, Page 134.7, https://doi.org/10.4049/jimmunol.202.Supp.134.7
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Abstract
The use of toll like receptor (TLR) agonists for immunotherapy remains under intense investigation. Activation of TLRs unleash the power of dendritic cells (DCs) to induce a robust antitumor CD8+ T cell response. However, the role of TLRs in CD8+ T cells has been largely overlooked. T cells do express endosomal TLR9, but it is not readily targetable in these non-phagocytic cells. Using the novel delivery platform of spherical nucleic acids (SNAs), we have devised a way to efficiently activate endosomal TLR9 by CpG, while simultaneously delivering tumor antigens to intracellular compartments in T cells. Activation of TLR9 in CD8+ T cells endows them with special properties. First, T cells themselves express appreciable levels of co-stimulatory molecules after activation of CpG derived from SNAs, thereby functioning as antigen presenting cells to cross-prime antigen-specific CD8+ T cells. Second, SNA activated T cells act as chaperones (T chaperones) of SNA material. Through exosomal transfer, T chaperones shuttle CpG and antigen, mouse or human, to bystander DCs for further cross-presentation of antigen. Third, antigen specific T chaperones are highly cytotoxic and resist tumor induced immune suppression. These combined effects of adoptive therapy using tumor antigen specific T chaperones achieve tumor regression in aggressive melanoma models without irradiation or cytokine supplementation, which complicate T cell-based therapies. T chaperones represent a novel cell-based therapy that co-delivers adjuvant and antigen to efficiently boost antitumor CD8+ T cell activity, eliminating the need for viral manipulation and shortens the long, and costly, production time associated with other T cell therapies.
