Immune checkpoint blockade (ICB) has demonstrated curative potential in several types of cancer, but only for a small number of patients. Thus, the identification of reliable and noninvasive biomarkers for predicting ICB responsiveness is an urgent unmet need. Here, we show that ICB increased tumor vessel perfusion in treatment-sensitive EO771 and MMTV-PyVT breast tumor as well as CT26 and MCA38 colon tumor models, but not in treatment-resistant MCaP0008 and 4T1 breast tumor models. In the sensitive tumor models, the ability of anti-cytotoxic T lymphocyte-associated protein 4 or anti-programmed cell death 1 therapy to increase vessel perfusion strongly correlated with its antitumor efficacy. Moreover, globally enhanced tumor vessel perfusion could be detected by Doppler ultrasonography before changes in tumor size, which predicted final therapeutic efficacy with more than 90% sensitivity and specificity (Fig. 1). Mechanistically, CD8⁺ T cell depletion, IFN-γ neutralization, or implantation of tumors in IFN-γ receptor knockout mice abrogated the vessel perfusion enhancement and antitumor effects of ICB. These results demonstrated that ICB increased vessel perfusion by promoting CD8⁺ T cell accumulation and IFN-γ production, indicating that increased vessel perfusion reflects the successful activation of antitumor T cell immunity by ICB. Our findings suggest that vessel perfusion can be used as a novel noninvasive indicator for predicting ICB responsiveness.

Based on these original findings, we propose a new mechanism of ICB therapy: ICB therapy activates CD8⁺ T cells, which in turn promotes the normalization of tumor blood vessels. The initial vascular normalization decreases immunosuppressive processes within the tumor microenvironment, facilitates the infiltration of effector T cells and improves their function, leading to further normalization of tumor blood vessels. This feedback loop between immune reprogramming and tumor vascular normalization reinforces itself, ultimately promoting immune-mediated tumor eradication (Fig. 2).

Link to papers:

https://www.jci.org/articles/view/96582

https://www.nature.com/articles/nri.2017.145

Link to Prof. Huang’ group: http://tangcenter.suda.edu.cn/en/ShowSingleFaculty.aspx?id=136