Augmenting Anticancer Immunity Through Combined Targeting of Angiogenic and PD-1/PD-L1 Pathways: Challenges and Opportunities

Abstract

Cancer immunotherapy (CIT) with antibodies targeting the programmed cell death 1 protein (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis have changed the standard of care in multiple cancers. However, durable antitumor responses have been observed in only a minority of patients, indicating the presence of other inhibitory mechanisms that act to restrain anticancer immunity. Therefore, new therapeutic strategies targeted against other immune suppressive mechanisms are needed to enhance anticancer immunity and maximize the clinical benefit of CIT in patients who are resistant to immune checkpoint inhibition. Preclinical and clinical studies have identified abnormalities in the tumor microenvironment (TME) that can negatively impact the efficacy of PD-1/PD-L1 blockade. Angiogenic factors such as vascular endothelial growth factor (VEGF) drive immunosuppression in the TME by inducing vascular abnormalities, suppressing antigen presentation and immune effector cells, or augmenting the immune suppressive activity of regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. In turn, immunosuppressive cells can drive angiogenesis, thereby creating a vicious cycle of suppressed antitumor immunity. VEGF-mediated immune suppression in the TME and its negative impact on the efficacy of CIT provide a therapeutic rationale to combine PD-1/PD-L1 antibodies with anti-VEGF drugs in order to normalize the TME. A multitude of clinical trials have been initiated to evaluate combinations of a PD-1/PD-L1 antibody with an anti-VEGF in a variety of cancers. Recently, the positive results from five Phase III studies in non-small cell lung cancer (adenocarcinoma), renal cell carcinoma, and hepatocellular carcinoma have shown that combinations of PD-1/PD-L1 antibodies and anti-VEGF agents significantly improved clinical outcomes compared with respective standards of care. Such combinations have been approved by health authorities and are now standard treatment options for renal cell carcinoma, non-small cell lung cancer, and hepatocellular carcinoma. A plethora of other randomized studies of similar combinations are currently ongoing. Here, we discuss the principle mechanisms of VEGF-mediated immunosuppression studied in preclinical models or as part of translational clinical studies. We also discuss data from recently reported randomized clinical trials. Finally, we discuss how these concepts and approaches can be further incorporated into clinical practice to improve immunotherapy outcomes for patients with cancer.

Keywords: angiogenesis; checkpoint inhibitor; programmed death ligand 1 (PD-L1); programmed death-1 (PD-1); tumor microenvironment; vascular endothelial growth factor (VEGF).

Figure 1

VEGF and PD-1/PD-L1 signaling axes. (A) VEGF ligands include VEGF-A, VEGF-B, VEGF-C, VEGF-D, and PlGF, which interact with a combination of various VEGFRs. Canonical VEGF signaling through VEGF-R1/R2 (with R2 being the dominant signaling receptor) regulates the activities of several kinases and ultimately guides cell proliferation, migration, survival, and vascular permeability during vasculogenesis and angiogenesis. Multiple inhibitors block VEGFA-induced signaling. Bevacizumab and ranibizumab bind VEGFA. The soluble chimeric receptor aflibercept binds VEGFA, PlGF, and VEGFB. The VEGFR2-specific monoclonal antibody ramucirumab prevents VEGFR2-dependent signaling. Numerous small molecule TKIs block VEGFR signaling. (B) Activated T cells express PD-1, which engages with its specific ligand (PD-L1 or PD-L2) to dampen activation. PD-1 axis blockade through the administration of an anti–PD-1 or anti–PD-L1 antibody prevents this inhibitory interaction and unleashes antitumoral T lymphocyte activity by promoting increased T-cell activation and proliferation, by enhancing their effector functions. APC, antigen-presenting cells; CTL, cytotoxic T lymphocytes; DC, dendritic cell; iDCs, immature dendritic cells; IL, interleukin; iMC, immature myeloid cells; M1, classical macrophages; M2, alternative macrophages; matDCs, mature dendritic cells; MDSC, myeloid-derived suppressor cell; PD-1, programmed cell death 1 protein; PD-L1, programed cell death ligand 1; PlGF, placental growth factor; TAM, tumor associated macrophages; TFG-β, transforming growth factor β; TKI, tyrosine kinase inhibitor; Treg, tumor-associated macrophages; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

Figure 2

Mechanisms of VEGF-mediated immunosuppression in the TME. Beyond its ability to mediate immune suppression via an abnormal tumor vasculature, increased VEGF levels can lead to immune suppression via inhibition of DC maturation, reduction of T-cell tumor infiltration, and promotion of inhibitory cell types in the TME. APC, antigen-presenting cells; CTLA, cytotoxic T lymphocyte associated; DC, dendritic cell; MHC, major histocompatibility complex; PD-1, programmed cell death 1 protein; PD-L1, programed cell death ligand 1; PlGF, placental growth factor; TME, tumor microenvironment; TCR, T-cell receptor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

Figure 3

PFS, OS, and ORR in patients with NSCLC with or without baseline liver metastases. Kaplan-Meier estimates of PFS and OS in patients with or without liver metastases at baseline in the intention-to-treat population for the ABCP vs. BCP treatment comparison and the ACP vs. BCP treatment comparison. Adapted from Reck et al. (154). ABCP, atezolizumab plus bevacizumab plus carboplatin plus paclitaxel; ACP, atezolizumab plus carboplatin plus paclitaxel; BCP, bevacizumab plus carboplatin plus paclitaxel; CI, confidence interval; HR, hazard ratio; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.