Increased vessel perfusion predicts the efficacy of immune checkpoint blockade

Abstract

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. 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.

Dual Programmed Death Receptor‐1 and Vascular Endothelial Growth Factor Receptor‐2 Blockade Promotes Vascular Normalization and Enhances Antitumor Immune Responses in Hepatocellular Carcinoma

“…For example, Tian et al demonstrated that—in a preventative setting—normalized vessel formation and antitumor immune responses were reciprocally regulated by CD4 + and not CD8 + cells in an IFN‐γ‐dependent manner in breast cancer models. This contrasted with data generated in an interventional setting, where Zheng et al showed that CD8 + T‐cell activation by ICB alone mediated the normalization of tumor vessels, albeit also in an IFN‐γ‐dependent manner.…”

“…This may be because antiangiogenesis (AA) can excessively prune vessels and increase hypoxia . Interestingly, a recent study has shown that anti‐PD‐1 therapy can increase blood perfusion of tumors by normalizing vessels in breast and colorectal cancer models . However, the effect of anti‐PD‐1 therapy—alone or with anti‐VEGF/R therapy—on HCC vasculature is unknown.…”

“…(4,9) Interestingly, a recent study has shown that anti-PD-1 therapy can increase blood perfusion of tumors by normalizing vessels in breast and colorectal cancer models. (19) However, the effect of anti-PD-1 therapy-alone or with anti-VEG-F/R therapy-on HCC vasculature is unknown. Understanding this effect is critically important as combination therapy may yield outcomes superior to either monotherapy.…”

Combining microenvironment normalization strategies to improve cancer immunotherapy

“…1). We simulate how antiangiogenic, stroma normalization, and immunotherapy treatments affect model components and compare model predictions with previous experimental studies (19,24,26,36,49). Furthermore, we use model predictions to provide guidelines for the optimal use of these three strategies and point out the gaps in our understanding.…”

“…In addition, hypoxia and acidity affect the function of T lymphocytes and other immune cells (14)(15)(16), whereas hypoperfusion and the dense/stiff TME is a physical barrier to T cell infiltration into the tumor (17,18). Indeed, increased perfusion has been related to improved ICB response (19).…”