Dual-mechanism based CTLs infiltration enhancement initiated by Nano-sapper potentiates immunotherapy against immune-excluded tumors

Abstract

The failure of immunotherapies in immune-excluded tumor (IET) is largely ascribed to the void of intratumoral cytotoxic T cells (CTLs). The major obstacles are the excessive stroma, defective vasculatures and the deficiency of signals recruiting CTLs. Here we report a dualmechanism based CTLs infiltration enhancer, Nano-sapper, which can simultaneously reduce the physical obstacles in tumor microenvironment and recruiting CTLs to potentiate immunotherapy in IET. Nano-sapper consists a core that co-loaded with antifibrotic phosphatesmodified α-mangostin and plasmid encoding immune-enhanced cytokine LIGHT. Through reversing the abnormal activated fibroblasts, decreasing collagen deposition, normalizing the intratumoral vasculatures, and in situ stimulating the lymphocyte-recruiting chemoattractants expression, Nano-sapper paves the road for the CTLs infiltration, induces the intratumoral tertiary lymphoid structures, thus reshapes tumor microenvironment and potentiates checkpoint inhibitor against IET. This study demonstrates that the combination of antifibrotic agent and immune-enhanced cytokine might represent a modality in promoting immunotherapy against IET.

Nano-immunotherapy for each stage of cancer cellular immunity: which, why, and what?

“…The secreted LIGHT recovered vessel functions and stimulated the expression of lymphocyte-recruiting chemo-attractants. Accordingly, MP and LIGHT synergistically improved CTL infiltration and supported local generation of a tumor-specific immune response 113 .…”

“…Once the TME has been reprogrammed by Nano-sapper, a variety of adaptive immune cells migrate to the PDAC and enhance the anti-tumor effects of α-PD-1. Adapted with permission from 113 , Copyright 2020 Springer Nature.…”

Targeting the tumor immune microenvironment with “nutraceuticals”: From bench to clinical trials

“…After nano-sapper treatment, tumor blood vessels were normalized; CD4 + and CD8 + T cells and B cells accumulated in the tumor site; and Tregs and macrophage numbers were decreased (Y. Huang et al, 2020). A similar strategy combining a CAFs-targeting biodegradable polymer nanoparticle loaded with α-mangostin was developed for use in pancreatic cancer.…”

Combined Application of Nanotechnology and Multiple Therapies with Tumor Immune Checkpoints

“…Therefore, integrating MP and PLICT into FHK peptide modified CAP (FHK- PLIGHT@cAMP) can synergistically improve the penetration of cytotoxic T lymphocytes and enhance the immune response of immune rejection tumors to ICB. [47] Recently, Stephanie Y. Tzeng and others have prepared a biodegradable nanoparticle that can genetically recombine tumor cells and their microenvironment so that tumor cells can induce immune-stimulating cytokines (IL-12) Co-expression with costimulatory molecules (4-1BBL) to exert the immune effect of tumor-associated antigen-presenting cells (tAPCs). In vivo and in vitro experiments have shown that anti-PD-1 checkpoint blockade and locally delivered tAPC programmed nanoparticles can significantly slow down the growth of tumor cells and even eliminate tumors, further realizing the systemic cell-mediated tumor-specific immunotherapy responses.…”