The Research Progress of Antiangiogenic Therapy, Immune Therapy and Tumor Microenvironment

Abstract

Anti-angiogenesis therapy, a promising strategy against cancer progression, is limited by drug-resistance, which could be attributed to changes within the tumor microenvironment. Studies have increasingly shown that combining anti-angiogenesis drugs with immunotherapy synergistically inhibits tumor growth and progression. Combination of anti-angiogenesis therapy and immunotherapy are well-established therapeutic options among solid tumors, such as non-small cell lung cancer, hepatic cell carcinoma, and renal cell carcinoma. However, this combination has achieved an unsatisfactory effect among some tumors, such as breast cancer, glioblastoma, and pancreatic ductal adenocarcinoma. Therefore, resistance to anti-angiogenesis agents, as well as a lack of biomarkers, remains a challenge. In this review, the current anti-angiogenesis therapies and corresponding drug-resistance, the relationship between tumor microenvironment and immunotherapy, and the latest progress on the combination of both therapeutic modalities are discussed. The aim of this review is to discuss whether the combination of anti-angiogenesis therapy and immunotherapy can exert synergistic antitumor effects, which can provide a basis to exploring new targets and developing more advanced strategies.

Keywords: antiangiogenic therapy; cancer biology; immune therapy; progress; tumor microenvironment.

Figure 1

Angiogenic signaling pathway and key anti-angiogenic targets in tumor angiogenesis. VEGFR、PDGFR、FGFR、c-kit、c-Met involved in the key molecular signal events(RAS-RAF-MEK-ERK signaling pathway and PI3K-AKT-mTOR signaling pathway) which plays a significant role in tumor proliferation, migration and invasion. All approved angiogenic tyrosine kinase inhibitors (TKIs) can target multiple receptors simultaneously and inhibit the transduction of downstream signaling.

Figure 2

The role of anti-VEGF treatment in the tumor microenvironment (TME). Tumor angiogenesis creates a hypoxic tumor microenvironment, which impedes T-effector cells、NK cells and DC cells infiltration into tumor, mediates tumor cell de-differentiation into CSCs, promotes proliferation of immunosuppressive cells, including Tregs and MDSCs, and polarizes TAMs to the immune inhibitory M2-like phenotype. After anti-VEGF treatment, the anti-tumor factors increase, and the pro-tumor factors are decreased. In summary, anti-VEGF treatment alleviate the immunosuppressive tumor microenvironment and improve cancer immunotherapy.