Angiogenesis and immune checkpoint dual blockade in combination with radiotherapy for treatment of solid cancers: opportunities and challenges

Abstract

Several immune checkpoint blockades (ICBs) capable of overcoming the immunosuppressive roles of the tumor immune microenvironment have been approved by the US Food and Drug Administration as front-line treatments of various tumor types. However, due to the considerable heterogeneity of solid tumor cells, inhibiting one target will only influence a portion of the tumor cells. One way to enhance the tumor-killing efficiency is to develop a multiagent therapeutic strategy targeting different aspects of tumor biology and the microenvironment to provide the maximal clinical benefit for patients with late-stage disease. One such strategy is the administration of anti-PD1, an ICB, in combination with the humanized monoclonal antibody bevacizumab, an anti-angiogenic therapy, to patients with recurrent/metastatic malignancies, including hepatocellular carcinoma, metastatic renal cell carcinoma, non-small cell lung cancer, and uterine cancer. Radiotherapy (RT), a critical component of solid cancer management, has the capacity to prime the immune system for an adaptive antitumor response. Here, we present an overview of the most recent published data in preclinical and clinical studies elucidating that RT could further potentiate the antitumor effects of immune checkpoint and angiogenesis dual blockade. In addition, we explore opportunities of triple combinational treatment, as well as discuss the challenges of validating biomarkers and the management of associated toxicity.

Fig. 1. Mechanistic rationale for immune checkpoint blockade in combination with anti-angiogenic agents.

Combinatorial therapy activates the immune response and suppresses the inhibitory immune signals by decreasing the expression of multiple immune checkpoints, increasing the ratio of anti-/pro-tumor immune cells, and alleviating hypoxia by normalizing tumor vasculature.

Fig. 2. Potential role of RT (fractionated low dose versus single high dose) on the tumor vasculature, tumor cell, and microenvironment.

A Main effects of RT on the immune response. High-dose RT triggers TREX1 resulting in clearance of cytosolic dsDNA. Multiple chemokines, cytokines, and growth factors secreted, upon RT, via cytosolic dsDNA/cGAS/STING signaling, promote the recruitment of immune cells. RT facilitates an immune response by inducing immunogenic cancer cell death and DAMPs, which activate antigen-presenting cells such as DCs PRRs, and prime CTLs, ultimately causing the release of cytokines, which not only exerts an immunosuppressive role by potentiating PD-L1 level on tumor cells but also drives immune cell recruitment by upregulating leukocyte adhesion molecules in the vessel wall. B Main effects of RT on the vasculature. Single high-dose RT triggers apoptosis and senescence of endothelial cells by upregulating ALK5 and sphingomyelinase, leading to vascular regression and collapse and eventual vasculogenesis and angiogenesis. Fractionated low-dose irradiation upregulates angiostimulatory growth factors, inducing vascular growth and tissue perfusion by potentiating diverse endothelial cell functions, such as migration, proliferation, and sprouting tube formation.