Synergistic effect of immune checkpoint blockade and anti-angiogenesis in cancer treatment

Abstract

Immune checkpoint inhibitor (ICI) activates host’s anti-tumor immune response by blocking negative regulatory immune signals. A series of clinical trials showed that ICI could effectively induce tumor regression in a subset of advanced cancer patients. In clinical practice, a main concerning for choosing ICI is the low response rate. Even though multiple predictive biomarkers such as PD-L1 expression, mismatch-repair deficiency, and status of tumor infiltrating lymphocytes have been adopted for patient selection, frequent resistance to ICI monotherapy has not been completely resolved. However, some recent studies indicated that ICI resistance could be alleviated by combination therapy with anti-angiogenesis treatment. Actually, anti-angiogenesis therapy not only prunes blood vessel which is essential to cancer growth and metastasis, but also reprograms the tumor immune microenvironment. Preclinical studies demonstrated that the efficacy of combination therapy of ICI and anti-angiogenesis was superior to monotherapy. In mice model, combination therapy could effectively increase the ratio of anti-tumor/pro-tumor immune cell and decrease the expression of multiple immune checkpoints more than PD-1. Based on exciting results from preclinical studies, many clinical trials were deployed to investigate the synergistic effect of the combination therapy and acquired promising outcome. This review summarized the latest understanding of ICI combined anti-angiogenesis therapy and highlighted the advances of relevant clinical trials.

Tumor Angiogenesis and Anti-Angiogenic Strategies for Cancer Treatment

“…The immune checkpoint molecules, namely the programmed cell death protein 1 (PD-1) and its ligand the programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4), are important components of the immune system which downregulate the T-cell immune function. By administering antibodies against these molecules, T cells are restored from their exhausted status and the tumor-killing activity is reestablished [141,142]. In this context, a preclinical study proved the synergetic effects of the combined anti-angiogenic and immune therapy.…”

The role of cancer-derived microRNAs in cancer immune escape

“…This immunosuppressive cytokine repertoire inhibits the functions of multiple effector cells, induces the differentiation of regulatory cells, and impedes the infiltration of T cells [43,44]. In addition, overexpressed immune checkpoints or their ligands such as PD-L1 on cancer cells promote the formation of exhausted TILs [45]. Moreover, some cancer cell-derived metabolites including indoleamine 2, 3-dioxygenase (IDO), arginase, and inhibitor of nuclear factor kappa-B kinase are greatly related to immune resistance in tumor as well [46][47][48].…”

Lactate dehydrogenase: a marker of diminished antitumor immunity

“…However, appropriately dosed anti-angiogenic therapy rather seems to normalize tumor vasculature, thereby temporarily improving tumor oxygenation. 75 As a result, anti-angiogenic therapy may reverse the immune suppressive effects of hypoxia. VEGF (receptor) inhibition, indeed, resulted in reduced regulatory T cell and MDSC recruitment to the tumor site and reduced the immune suppressive capacity of MDSCs and macrophages.…”

“…83,84 The combination of anti-angiogenic therapy and checkpoint inhibitors is currently also being studied in many other tumor types. 75 Previous studies on the combination of VEGF inhibitors and checkpoint inhibitors did not report on LDH levels in relation to response. It appears relevant to specifically study the combination of antiangiogenic agents and checkpoint inhibitors in patients with elevated LDH levels, considering their responses to anti-angiogenic therapy and the association between serum LDH levels and tumor VEGF (receptor) expression.…”