Adv Mater biomimetic lipoprotein system remodels tumor physical barrier and enhances T cell infiltration

Immunotherapy based on immune checkpoint inhibitors (ICIs) is emerging as a revolutionary oncology treatment option, but it is only available for a small subset of cancer patients
.
The clinical response to ICIs mainly relies on the recognition and killing of tumor cells by effector T lymphocytes (CTLs) infiltrating tumor tissues
.
However, CTL infiltration in tumor tissue is very limited, and the complex intratumoral physical barrier severely hinders CTL infiltration, impairing the therapeutic effect of ICIs
.
Therefore, how to reshape the physical barrier in the tumor to enhance the infiltration of CTL has become an urgent problem to be solved to improve the immunotherapy mediated by ICIs
.

On January 29, 2022, Adv Mater , with the title "Bioinspired lipoproteins of furoxans-oxaliplatin remodels physical barriers in tumor to potentiate T-cell infiltration", published online researcher Zhang Zhiwen, Shanghai Institute of Materia Medica researcher Li Yaping and The latest research results of the team of Professor Wang Siling of Shenyang Pharmaceutical University
.
This study proposes and confirms a new strategy to use the biomimetic lipoprotein system to efficiently deliver nitric oxide (NO) donor-oxaliplatin prodrugs to promote CTL intratumoral infiltration and enhance ICIs immunotherapy by remodeling the tumor physical barrier
.

The detection of breast and colon cancer clinical samples found that various extracellular matrix components were widely present in the tumor site, but CD8+ T infiltration was severely lacking
.
Based on this, the research team designed and synthesized an intracellular reduction-responsive NO donor-oxaliplatin prodrug (FO), and constructed a biomimetic lipoprotein system (S-LFO) that efficiently targets various stromal cells in the tumor
.
It was found that S-LFO can efficiently accumulate at the tumor site, penetrate deep into the tumor, and reach stromal cells such as intratumoral tumor-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and vascular endothelial cells (ECs)
.
S-LFO treatment can significantly promote the normalization of tumor blood vessels, perfusion capacity and blood vessel density, reduce the ratio of TAMs and CAFs, remove major extracellular matrix components such as Collagen, Fibronectin and chondroitin sulfate, and pave the way for promoting the intratumoral infiltration of CTL.
road
.
Further research found that S-LFO can significantly increase the proportion of CD3+CD8+ T cells and the expression of IFN-γ and Granzyme B subtypes in the tumor site, which were increased by 2.
96, 5.
02 and 8.
65 times respectively compared with the control group, and significantly promoted CD8+ T cells.
The ability of cells to infiltrate and spread into the intratumoral 4T1-GFP cancer cell area, and then in tumor models such as pancreatic cancer PANC02, breast cancer 4T1 and colorectal cancer CT26, the combination with aPD-L1 significantly enhanced the inhibition of tumor growth and prolonged survival.
's curative effect
.
This strategy provides a novel approach for remodeling the tumor stromal barrier to enhance CTL infiltration and enhance the immunotherapeutic effect of ICIs
.

 

Figure 1 S-LFO remodels the tumor stromal barrier and promotes T cell infiltration

Figure 2 S-LFO promotes intratumoral infiltration of CTLs

　　Researcher Zhang Zhiwen and Li Yaping from Shanghai Institute of Materia Medica and Professor Wang Siling from Shenyang Pharmaceutical University are the co-corresponding authors of this article.
Doctors Wang Yuqi, Xie Honglei and master student Wu Yao are the co-first authors
.
The research was supported by the National Natural Science Foundation of China, the Natural Science Foundation of Shandong Province, and the Fudan-SIMM Joint Research Fund
.

　　Full text link: https://onlinelibrary.
wiley.
com/doi/10.
1002/adma.
202110614

(Contributed by: Li Yaping Research Group; Contributed by: Zhang Zhiwen)