Abstract
Blocking the immune evasion mechanism of tumor cells has become an attractive means for treating cancers. However, the usage of a drug such as nivolumab (αPD-1), which blocks programmed cell death protein 1 (PD-1), turned out to be only effective against certain types of cancer. Especially, vascular abnormal structures of which deter delivery route by leakage and cause the poor perfusion were considered to be environment unfavorable to T cells and immune checkpoint blockade (ICB) delivery within the tumor microenvironment (TME). Herein, we report stabilization of tumor blood vessels by endothelial dysfunctional blocker CU06-1004, which modified the TME and showed synergistic effects with immunotherapy anti-PD-1 antibody. CU06-1004 combination therapy consistently prolonged the survival of tumor-bearing mice by decreasing tumor growth. T-cell infiltration increased in the tumors of the combination group, with cytotoxic CD8+ T cell activity within the tumor parenchyma upregulated compared with anti-PD-1 monotherapy. Tumor inhibition was associated with reduced hypoxia and reduced vessel density in the central region of the tumor. These effects correlated significantly with enhanced expression of IFN gamma and PD-L1 in tumors. Taken together, our findings suggest that CU06-1004 is a potential candidate drug capable of improving therapeutic efficacy of anti-PD-1 through beneficial changes in the TME.
Highlights
Immunotherapy is an innovative way of treating cancers
We demonstrate that direct drug delivery of CU06-1004 results in tumor-infiltrating immune cell populations containing natural killer (NK) and T cells and tumor apoptosis induced by increased CD8+ T cell activity
Our findings indicate that CU06-1004, which blocks endothelial dysfunction, improves efficacy of immune checkpoint blockade (ICB) in the tumor microenvironment (TME) compared with anti-Programmed cell death 1 (PD-1) therapy alone
Summary
Immunotherapy is an innovative way of treating cancers. response rates and effects vary among tumors expressing specific biomarkers [1, 2]. Tumors can evade T cells by expressing immunosuppressive molecules or receptors, such as programmed death-ligand 1 (PD-L1) [4]. Programmed cell death 1 (PD-1) binds PD-L1 and is expressed on the surface of immune cells, including activated T cells, B cells, monocytes, natural killer (NK) cells, and dendritic cells [5]. Immune checkpoint blockade (ICB) targeting PD-L1/PD-1, galectin-9/TIM-3, IDO1, LAG-3, and CTLA4 seeks to increase the number and activity of CTLs in tumors [7]. These therapies share some properties but commonly face drug delivery challenges [8, 9]. Enhanced delivery technologies, increased interactions of drugs with target proteins, and reduced extratumoral drug release, may improve efficacy [10]
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