Studies on xenograft models of melanoma or breast cancer 7 showed that sunitinib, in fact, increased metastasis and shortened the survival of the tumor-bearing mice. Recently, the China Food and Drug Administration CFDA approved the single agent anlotinib as a third-line treatment for patients with advanced NSCLC.

Compared to placebo, anlotinib has been demonstrated to improve both progression-free survival PFS and overall survival OS in a phase III trial among patients with advanced non-small-cell lung cancer NSCLC , despite progression of cancer after two lines of prior treatments.

Among normal healthy human beings, angiogenic balance exists due to regulation of the vascular endothelial growth factors VEGFs - angiostatin and the angiogenic molecules.

However, in tumors, this balance becomes converted to pro-angiogenesis. VEGFs, which play pivotal roles in wound healing and angiogenesis, consist of five members, VEGF A-E.

VEGF works by binding to the vascular endothelial growth factor receptor VEGFR , which is comprised of three tyrosine kinases.

VEGA-A is up-regulated in most solid tumors, including breast cancer and lung cancer, which makes it a significant target of anti-angiogenesis drugs 8.

The first FDA-approved anti-angiogenesis treatment was kinase inhibitors that targeted the VEGFR. Subsequently, antibodies against VEGF-Trap and VEGFR2 have been approved 9.

Hepatocyte growth factor HGF promotes cell survival, enhances cell invasion ability, and facilitates epithelial-mesenchymal transition by activating the mesenchymal-epithelial transformation factor c-MET signaling pathway in endothelial cells.

To date, researchers have discovered that c-MET and HGF are overexpressed in a number of tumors, which has led to abnormal gene amplification, activation of transcription or hypoxia microenvironment.

However, clinical efficacy of VEGF-targeted drugs has vital limitations. Although phase 3 trials have demonstrated that use of anti-angiogenic agents leads to significant improvements in overall survival OS for several cancers, such as advanced-stage CRC, RCC, and HCC, it is also associated with a failure to improve OS in other cancers, such as breast cancer, glioblastoma, pancreatic ductal adenocarcinoma PDAC and prostate cancer 10 — Carvalho B et al.

Their data indicates that c-Met and VEGFR2 overexpression play a significant role in the development of glioblastoma early resistance and may predict poorer responses to anti-angiogenic therapies Either anti-VEGFs or anti-VEGFRs or other nonspecific tyrosine kinase inhibitors ultimately shut down tumor blood supply and drive tumor necrosis.

Necrosis usually occurs in the central part of the tumor, and the surrounding tumor cells remain alive as they are benefited by nutrition delivered by nearby normal blood vessels. As a result, most vascular disruptor therapy does not completely prevent tumor growth.

This may be one of the reasons why antiangiogenic therapy improves therapeutic outcomes, while beneficial effects remain short 9. In addition, primary or acquired resistance contributes more to failure of anti-angiogenesis treatment. Tina Cascone used mouse-and human-specific profiling of human NSCLC xenografts in mice in order to investigate stromal and tumor cell changes that occur in tumors that acquire resistance to anti-angiogenesis treatment.

Researchers found that changes in gene expression, particularly changes in expression of angiogenesis-related genes, occurred predominantly in stromal cells, but not in tumor cells. The observation reinforces the notion that tumor stroma may play an important and potentially dominant role, in at least some circumstances — in VEGF inhibitor resistance Furthermore, extrinsic mechanisms have also been shown to be involved in resistance to antiangiogenic therapy, including changes in the tumor microenvironment TME , the presence of cancer stem cells CSCs , and tumor immunosuppression, which significantly limits their clinical value 15 , The tumor microenvironment TME is composed of immune cells, stromal cells, extracellular matrix ECM , blood vessels, tumor cells, lymphatic vessels and CSCs.

The constant changes that occur in the various components of the TME result in its complexity and heterogeneity.

TME is associated with multiple processes, including proliferation, angiogenesis, apoptosis, and immune surveillance. The stromal cells, particularly cancer-associated fibroblasts CAFs , can promote tumor cell survival mainly by recruiting immune cells into the TME, and promote invasion by constructing a hypoxic environment.

Tumor-driven hypoxia, increased inflammation, or MMPs overexpression in the TME induces alterations in the ECM, following the tumor biological behavior of evading apoptosis, elevating invasion and metastasis 17 , In addition, ECM components can regulate the cancer-immunity cycle. The above TME changes cause tumor progression and drug resistance As tumors generally tend to be hypoxic, prolonged use of anti-angiogenesis drugs can often aggravate hypoxia 20 , As previously reported, the upregulation of hypoxic inducible factor 1a HIF-1a is also responsible for heterogeneity of breast cancer, lung cancer, cervical carcinoma, and gliomas 22 — Hypoxia-induced upregulation of HIF-1a can mediate tumor cell de-differentiation into CSCs, which is a primary mechanism that underlies resistance to anti-angiogenesis therapy 25 , In addition, HIF-1a upregulates the expression of nuclear factor-kβ and leads to increased recruitment of monocytes and tumor-associated macrophages TAMs , including polarization of the M2 phenotype TAMs, which promotes recurrence and metastasis The immune system can have a dual effect in cancer biology, including pro-tumorigenic and anti-tumorigenic effect.

The immune surveillance system identifies, kills, and removes tumor cells from the body. Unsurprisingly, the host immune system is often disrupted and creates an immune imbalance among cancer patients. Tumor cells can camouflage themselves in order to hide from immune cells, thus avoiding being discovered.

Numerous cellular and molecular mechanisms have been shown to be responsible for tumor evasion 28 , Immunosuppressive cells, such as T-regs, TAMs, and MDSCs frequently accumulate within the TME, which is associated with an unfavorable prognosis.

When there are a large number of immune cells in tumor tissues, such as T-regs, MDSCs, TAMs, and DCs, they can promote an immunosuppressive microenvironment and participate in immune escape. 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.

Additionally, primary drug resistance due to a lack of tumor-infiltrating lymphocytes in the tumor should not be ignored. Studies have shown that patients that receive immunotherapy with higher Ang-2 expression tend to have poorer clinical outcomes. This suggests that the Ang-2 pathway is another cause of immunotherapy resistance 34 , Under normal circumstances, the immune system can recognize and eliminate tumor cells within the tumor microenvironment.

Immunotherapy has heralded a new era of oncotherapy and aims to either directly eliminate cancer cells or activate the host immune response. It is mediated through anti-cancer cell vaccines and antibodies, cytokines, adoptive immune cell transfer and immune checkpoint blockers ICBs.

Tumor immunotherapy includes monoclonal antibody immune checkpoint inhibitors 36 , therapeutic antibodies, cancer vaccines, cell therapy and small molecule inhibitors.

In recent years, cancer immunotherapy has continued to progress. At present, this treatment method has shown strong anti-tumor activity in the treatment of solid tumors such as melanoma, NSCLC, kidney cancer, and prostate cancer.

Furthermore, immunotherapy drugs have been approved by the US FDA Food and Drug Administration for clinical application Moreover, increasing evidence has shown that overexpression of vascular growth factors can activate immunosuppressive cells directly and suppress immune effector cells to alter the immunosuppressive microenvironment.

The relationship between angiogenesis and immune therapy is a complicated interplay. Anti-angiogenic agents can stimulate the immune system and improve the immunosuppressive environment, while immunotherapy can also have anti-angiogenesis effects. Therefore, there is a synergistic relationship between the two treatment methods 38 , Tumor cells can evade T cell-mediated killing by up-regulating the interaction of PD-L1 with the inhibitory receptor PD-1, which is expressed on tumor-infiltrating T-cells.

Tumor cells can evade T cell-mediated killing by upregulating the interaction of ligands such as PD-L1 with the inhibitory receptor PD-1, CTLA-4, and LAG-3, which are expressed on tumor-infiltrating T-cells It is inevitable that patients will develop resistance to immune checkpoint inhibitors due to a lack of PD-L1 and the inhibitory effect in the TME.

Facing a complex TME, the key strategy is to inhibit angiogenesis, and an effective immune response The formation of blood vessels in malignant tumors is largely caused by hypoxia and the excessive secretion of VEGF. A case study of immune checkpoint inhibitors combined with anti-angiogenic drugs in the treatment of metastatic renal cell carcinoma demonstrated that antigen-specific T cell migration and expression of MHC-1 and PD-L1 were increased.

Furthermore, anti-tumor activity was enhanced with less toxicity Tumor blood vessels were found to be highly abnormal, with tumor vessels showing structural abnormalities, leading to hypoxia, acidity, and a high interstitial fluid pressure microenvironment. These microenvironmental abnormalities can affect immune cell proliferation, infiltration, survival, and function Myeloid-derived suppressor cells MDSCs are one of the most important stromal cells of the TME, and protect tumor cells from the host immune system by suppressing T-cell function There is evidence to support the hypothesis that anti-angiogenic therapy and immunotherapy act synergistically GM-CSF, a potent cytokine promoting the differentiation of myeloid cells such as dendritic cells, macrophages and granulocytes, which elicits antitumor immunity by enhance tumor antigen presentation to T cells, has been proven to be effective across numerous clinical trials 46 — And Sylvie et al.

also included that human GFs in vitro actively inhibit the differentiation of monocyte-derived dendritic cells through the secretion of IL-6 and VEGF, limiting the immunotherapy of GM-CSF Furthermore, it also promotes proliferation of immunosuppressive cells, such as Tregs and MDSCs, and inhibits DC maturation, and restricts the development of T lymphocytes from the lymphoid progenitors 30 , 53 — A study 56 on three different NSCLC animal models demonstrated that combining adoptive transfer of cytokine-induced killer CIK cells with recombinant human endostatin significantly inhibited angiogenesis and tumor growth, whereas neither was effective when used alone.

Lydia Meder et al. conducted an experiment on five groups on the combined use of vehicle, IgG, VEGF inhibitor, PD-L1 inhibitor, VEGF inhibitor, and PD-L1 inhibitor in a mouse model of small cell lung cancer. The results indicate that treatment with VEGF, compared to any other treatment methods, the combination of inhibitor and PD-L1 inhibitor greatly improved PFS and OS in mice Yasuda et al.

reported that in a mouse model of colon cancer, the combined use of PD-1 inhibitors and VEGFR2 inhibitors demonstrated no obvious toxicity. Compared to the control group, the experimental group drugs were found to better inhibit tumor growth.

The author believes that the combined use of inhibitors can produce a synergistic anti-tumor effect in the body through a variety of mechanisms, including anti-VEGFR2 therapy resulted in a significant decrease of tumor micro vessels as well as reducing tumor vasculature and anti-PD-1 mAb treatment enhanced the infiltration of T cells into tumors.

And that the two drugs are not mutually exclusive Since immunotherapy has been proved to be effective against CSCs and the immunosuppressive TME, it is reasonable to surmise that a combination of anti-angiogenesis and immunotherapies would have a synergistic effect against recalcitrant tumors.

Indeed, studies have shown that 38 targeting the angiogenic factor VEGF, as well as its receptors, stimulates onco-immunity, since VEGF is known to be involved in the immune escape of tumors.

The VEGF signaling pathway can abrogate the effects of anti-tumor therapy via various mechanisms. Usually, is LFA1 that can interact on ICAM1. LFA1 is expressed on lymphocytes and it is a crucial for T cell entry into mammalian lymph nodes and tissues while ICAM1 on tumor target cells or endothelial cells Previous study showed that clustering of ICAM-1 was indeed prevented by VEGF and a reduced induction of ICAM-1 and VCAM-1 mRNA transcripts by TNF in the presence of VEGF Therefore, blocking VEGF and its receptor can help stimulate immune responses and improve immunotherapy outcomes.

Similarly, sunitinib inhibited the expansion of Tregs and MDSCs in patients with renal cell carcinoma 30 , 63 , In a mouse model of colon cancer, anti-PD-1 monoclonal antibodies and VEGFR2 resulted in significantly greater tumor inhibition compared to either monotherapy The relationship between angiogenesis and immune therapy has been suggested to be a complicated interplay Anti-angiogenic agents are known to stimulate the immune system and improve the immune suppression environment Furthermore, immunotherapy can also cause anti-angiogenesis effects, and there is a synergistic relationship between the two treatment methods Tumor cells can evade T cell-mediated killing by up-regulating the interaction of PD-L1 with the inhibitory receptor PD-1 that is expressed on tumor-infiltrating T cells.

Thus, it is inevitable that patients develop resistance to immune checkpoint inhibitors due to a lack of PD-L1 and the inhibitory effect in the tumor microenvironment. The therapy should inhibit angiogenesis, on the other hand trigger anti-tumor immunity The formation of blood vessels in malignant tumors is mainly caused by hypoxia and excessive secretion of vascular endothelial growth factor VEGF.

Recently, an accumulating number of clinical trials have been conducted to explore the efficacy of the combination of anti-angiogenesis and immunotherapy Table 1. Table 1 Principal clinical trials for the approval of antiangiogenic and or immunotherapy agents.

In a phase 3 clinical trial IMpower NCT , patients with metastatic non-squamous NSCLC ns-NSCLC were treated with a combination of Atezolizumab to Bevacizumab-based chemotherapy, including three groups: 1 Atezolizumab, Carboplatin, and Paclitaxel ACP ; 2 Atezolizumab, Bevacizumab, Carboplatin and Paclitaxel ABCP ; 3 Bevacizumab, Carboplatin and Paclitaxel BCP.

The results demonstrated that the ABCP group had significantly improved PFS and OS, with an average of 8.

The median OS was not estimated in the ABCP, but it was In addition, patients with advanced NSCLC receiving treatment with a combination of Nivolumab and Bevacizumab were recruited for a phase 1 study NCT , which aimed to evaluate whether the combination therapy improves PFS and OS.

The experimental results indicate that the combined treatment group had significant safety, and the incidence of grade 3 and above adverse reactions is low. Therefore, it has shown excellent therapeutic effects compared to the single-agent treatment group The combined treatment group had a median PFS of Additionally, the median OS of the combined treatment group was In , results of the phase 1 study NCT were reported.

Among the total 27 enrolled patients with previously treated advanced NSCLC that received Ramucirumab plus Pembrolizumab, 8 patients achieved an objective response.

Another phase 1 study NCT indicated that the combination of Ramucirumab plus Durvalumab led to an enhancement of preliminary antitumor activity in heavy pre-treated NSCLC patients with a median PFS of 1. A first randomized phase 2 IMmotion study NCT for patients with previously untreated mRCC treated with Atezolizumab combination Bevacizumab or single Atezolizumab or single sunitinib showed that the PFS of this combination group significantly improved within the population, whatever the PD-L1 status Immunotherapy with PD-1 and PD-L1 inhibitors or combined with antiangiogenic therapy i.

VEGF inhibitors or CTLA-4 antibodies has become a first line therapy for advanced RCC patients Another phase 3 study NCT validated that the combination of Avelumab plus axitinib enhanced the curative effect in patients with advanced RCC, leading to remarkable improvement in median PFS In , a pivotal phase 3 study NCT demonstrated that Avelumab or Pembrolizumab Plus axitinib were more efficacious than sunitinib, a previous standard of care.

This study recruited metastatic renal cell carcinoma mRCC patients with results showing an improvement in PFS, a high response rate, and a low rate of intrinsic resistance Phase 1 study NCT of the VEGFR2 inhibitor apatinib plus anti-PD1 antibody SHR in patients with advanced hepatocellular carcinoma HCC has demonstrated manageable toxicity and encouraged clinical activity at recommended single-agent doses of both drugs These cohort results suggest that Nivolumab, plus Ipilimumab, may provide an improved ORR and OS, especially in arm A lower dose Nivolumab and higher dose Ipilimumab , relative to anti-PD-L1 monotherapy The combination of lenvatinib plus Pembrolizumab for unresectable HCC uHCC patients in the Phase 1b trial NCT represented a promising antitumor activity with an ORR of Moreover, an ongoing double-blind randomized controlled phase 3 study NCT of lenvatinib plus Pembrolizumab treatment of uHCC is currently being undertaken Imbrave NCT , a randomized, multicenter phase 3 clinical study aims to evaluate the efficacy and safety of Atezolizumab plus Bevacizumab versus Sorafenib among patients with advanced HCC.

The results indicated that, among patients in the combination group and in the Sorafenib group with HCC, the combination group showed a remarkable improvement in median PFS and OS with tolerated and controllable toxicity, compared to the Sorafenib group The results from this study indicated that the treatment had an ORR of Preliminary results from the phase 1 clinical trial NCT showed that Ipilimumab CTLA-4 antibody plus Bevacizumab VEGF inhibitors in patients with metastatic melanoma MM had favorable clinical outcomes, for reasons of increasing tumor vascular expression of ICAM-1 and VCAM-1 and lymphocyte infiltration in tumors Another open-label phase 1b trial NCT validated the efficacy of axitinib in combination with Toripalimab among patients with advanced melanoma with an ORR of In addition, a phase 2 study NCT in mCRC patients also demonstrated that the addition of Atezolizumab to Bevacizumab, as well as capecitabine, improved the median PFS of 4.

The results demonstrated that the combination was generally well tolerated, with an acceptable toxicity profile without any unexpected findings Anti-tumor angiogenesis was found to be favorable to T-cell infiltration and drug delivery to the tumor, thereby enhancing the efficacy of immunotherapy.

Additionally, immunotherapy can also increase tumor vascular normalization and form positive feedback to anti-angiogenesis. Therefore, the combination of anti-angiogenic agents and immunotherapy provides a new therapeutic approach for tumor patients.

A large number of studies have demonstrated that the combination therapy has good clinical application prospects. However, the relationship between tumor angiogenesis and immune response is intricate, and some tough problems still need to be solved for future practical application.

Firstly, there is no way to identify tumor patients that can benefit from combination therapy 93 , and anti-angiogenesis therapy has a lack of biomarkers, as mentioned above. In order to address the problem, oncologists have to identify the biomarkers that can be associated with patient groups that would be advantaged with this therapy.

Secondly, the dose of each drug, the optimal sequence, and the time of the combination also remain significant. The high or low dose, simultaneous or sequential treatment, will have an effect on the efficacy of the combination therapy.

Furthermore, studies have demonstrated that high doses of anti-angiogenic drugs can directly damage tumor blood vessels, which results in more serious disturbances of tumor microenvironment, such as hypoxia and immunosuppression Therefore, it is necessary to choose the appropriate drug dosage, and optimize the schedule of tumor immunotherapy and anti-angiogenesis therapy in order to obtain improved anticancer efficacy.

Moreover, the most frequent side effect of anti-angiogenic is hypertension Therefore, primary or acquired resistance, including non-upregulation VEGF in tumors, changes in the TME, the presence of CSCs, and the patient with hypertension contribute to anti-angiogenesis failure Besides, resistance to immunotherapy, including lack of tumor-infiltrating lymphocytes in the tumor, accumulating immunosuppressive cells in the TME and secreting immunosuppressive cytokines in the tumor cells, contributes significantly to failure of immunotherapy.

FL and JH contributed to the study design. HH and YC were responsible for data collection. ST, YH, and SF drafted and prepared the manuscript. SW worked for the table and figures. All authors participated in the data interpretation and contributed to the manuscript writing with important intellectual input.

All authors approved the final version of the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Lancet Oncol 15 2 — Garon EB, Ciuleanu T-E, Arrieta O, Prabhash K, Syrigos KN, Goksel T, et al. The U. Food and Drug Administration FDA has approved a number of angiogenesis inhibitors to treat cancer.

Most of these are targeted therapies that were developed specifically to target VEGF, its receptor, or other specific molecules involved in angiogenesis. Approved angiogenesis inhibitors include:. Side effects of treatment with VEGF-targeting angiogenesis inhibitors can include hemorrhage , clots in the arteries with resultant stroke or heart attack , hypertension , impaired wound healing, reversible posterior leukoencephalopathy syndrome a brain disorder , and protein in the urine.

Gastrointestinal perforation and fistulas also appear to be rare side effects of some angiogenesis inhibitors. Antiangiogenesis agents that target the VEGF receptor have additional side effects, including fatigue, diarrhea, biochemical hypothyroidism , hand-foot syndrome , cardiac failure, and hair changes.

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