Temporal responsive vesicle-INFγ aptamer-PEI/HA system targeted activation of B-CD4T-Tfh-CD8T cells cascade inhibits TNBC progression

Abstract

Like other tumors, triple-negative breast cancer (TNBC) exhibits immune evasion characteristics, but the activation of an appropriate immune cascade can effectively suppress TNBC progression. This article focuses on enhancing the cytotoxicity of CD8 T cells as an entry point. In TNBC patients and immunodeficient mouse models, it was found that the proportions of specific CD95^hiGL7^hiB (acB), CD44^hiCD69^hiCD4 T (acCD4 T), CD44^hiICOS^hiPSGL1^loPD1^hi CXCR5^hiBCL6^hiTfh (acTfh), and PD1^hiGranzyme B^hiCD8 T (acCD8 T) cells are negatively correlated with tumor progression. Based on the pathological features of localized hypoxia and high lysyl hydroxylase 2(LH2) expression in TNBC, and utilizing the oxygen concentration responsiveness of nitroimidazoles, the homing targeting of cell-derived vesicles, the proteolytic activity of LH2 enzyme on substrate peptides, and the targeted inhibitory effect of nucleic acid aptamers, based on a temporal response strategy, this article designs a composite system of acTfh and primary TNBC cells derived vesicles, interferon gamma (INF-γ) aptamer, hyaluronic acid and polyethyleneimine. This system encapsulates co-stimulatory antigens for acB, acCD4 T, and acCD8 T cells, along with an interleukin 21 (IL21) overexpression plasmid. It can sequentially respond to hypoxia, LH2 enzyme, and IFNγ in TNBC tissues, thereby targeting the promotion of antigen secretion by TNBC cells, activating and expanding acB, acCD4 T, and acCD8 T cells. It activates acB to promote the differentiation of acCD4 T into acTfh cells, inhibits the tumor-promoting escape function of IFNγ produced by acCD4 T cells, targets the promotion of IL21 secretion by acTfh cells, and ultimately activates the cytotoxicity of acCD8 T cells to kill tumor cells. The temporal response strategy of this composite nanosystem offers a potential new approach for the immune treatment of TNBC in the future.