Targeting folate receptor β positive tumor-associated macrophages in lung cancer with a folate-modified liposomal complex

Abstract

Tumor-associated macrophages (TAMs) facilitate cancer progression by promoting tumor invasion, angiogenesis, metastasis, inflammatory responses, and immunosuppression. Folate receptor β (FRβ) is overexpressed in TAMs. However, the clinical significance of FRβ-positive macrophages in lung cancer remains poorly understood. In this study, we verified that FRβ overexpression in lung cancer TAMs was associated with poor prognosis. We utilized a folate-modified lipoplex comprising a folatemodified liposome (F-PLP) delivering a BIM-S plasmid to target both lung cancer cells and FRβ-positive macrophages in the tumor microenvironment. Transfection of LL/2 cells and MH-S cells with F-PLP/pBIM induced cell apoptosis. Injection of F-PLP/pBIM into LL/2 and A549 lung cancer models significantly depleted FRβ-positive macrophages and reduced tumor growth. Treatment of tumor-bearing mice with F-PLP/pBIM significantly inhibited tumor growth in vivo by inducing tumor cell and macrophage apoptosis, reducing tumor proliferation, and inhibiting tumor angiogenesis. In addition, a preliminary safety evaluation demonstrated a good safety profile of F-PLP/pBIM as a gene therapy administered intravenously. This work describes a novel application of lipoplexes in lung cancer targeted therapy that influences the tumor microenvironment by targeting TAMs.

Novel zwitterionic vectors: Multi-functional delivery systems for therapeutic genes and drugs

“…So far, many therapeutic genes are in clinical trials, and some have even been approved for marketing [161] , [162] . However, to send the therapeutic genetic molecules to the desired sites and ensure they could transcript and translate into functional proteins successfully, safe and effective carriers are indispensable [163] , [164] , [165] . The available gene delivery vectors at present generally include viral vectors, non-viral cationic polymers and inorganic mental materials [166] , [167] , [168] .…”

CAR T Cell Therapy for Solid Tumors: Bright Future or Dark Reality?

“…While FAP-CAR T cells had potent antitumor activity in preclinical models, some safety concerns were raised due to FAP expression on stromal cells in healthy tissues; nevertheless, this approach has been translated into the clinic. [258][259][260][261] TAMs have been targeted with CD123-or folate receptor b (FRb)-CAR T cells in preclinical models, 262,263 and CSF1R-CARs have been developed, opening up the possibility to target CSF1R-positive TAMs. 264 MDSCs express high levels of NKG2D ligands, and in one preclinical model, combining NKG2D-CAR NK cells with GD2-CAR T cells resulted in improved antitumor activity for neuroblastoma.…”

Nanomedicine in lung cancer: Current states of overcoming drug resistance and improving cancer immunotherapy

“…BIM‐S is the most potent isoform of BCL‐2‐interacting mediator of cell death (BIM) which plays an important role in cell apoptosis following effective targeted therapy and increasing BIM expression helps relieve resistance to targeted therapies. In vivo, the liposome showed significant inhibition of tumor growth via induction of tumor cell and macrophage apoptosis, reduction of tumor proliferation, and inhibition of tumor angiogenesis (Tie et al, 2020). In addition, some immunogenic NPs can effectively recruit macrophages and enhance the immune response.…”