Open in another window Scientific Rationale for Combination Immunotherapy with PD-1/PD-L1 Antibody plus Anti-VEGF/Molecular Targeted Agent High levels of vascular endothelial growth factor (VEGF) released from hypoxic tumor cells and the vascular endothelium induce angiogenesis, thereby contributing to proliferation, invasion, and metastasis of cancer cells. cells buy PSI-7977 (DCs). It decreases the number of DCs and inhibits their maturation, thereby suppressing the antigen-presenting ability of DCs in the priming phase. Therefore, despite their presence, neoantigens are not shown on DCs, as well as the activation and proliferation of CD8-positive cells are impaired. Furthermore, cells upregulated by VEGF (Tregs, TAMs, and MDSCs) suppress the proliferation and effector function of Compact disc8-positive cells. Although Compact disc8-positive cells are buy PSI-7977 triggered via antigen demonstration, VEGF-induced irregular tumor angiogenesis inhibits infiltration and trafficking of turned on CD8-positive cells towards the cancer cells. This qualified prospects to the forming of a tumor microenvironment wherein T-cells in the effector stage are disarmed. Furthermore, the discharge of immunosuppressive cytokines (IL-10, TGF-) from these immunosuppressive cells (Tregs, MDSCs, and TAMs) augments the microenvironment and enables immune escape, inhibiting DC maturation and activation therefore, organic killer cell activation, and T-cell proliferation and activation, and creating an immunosuppressive microenvironment [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24] (Fig. ?(Fig.1,1, ?,2).2). The cancer-immunity routine is a series of antitumor immune system reactions initiated upon demonstration by DCs of neoantigen peptides released by necrotic tumor cells, and comprises seven measures: (1) launch of tumor cell antigens, (2) tumor antigen demonstration by DCs, (3) priming and activation of T-cells, (4) trafficking of T-cells to tumors, (5) infiltration of T-cells into tumors, (6) reputation of tumor cells by T-cells, and (7) eliminating of tumor cells (Fig. ?(Fig.3).3). VEGF buy PSI-7977 disrupts this cancer-immunity routine by inducing immune system escape through the mechanisms described earlier at almost every step of the cycle [4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 25, 26] (Fig. ?(Fig.4).4). In the liver, hepatic interstitial cells (e.g., Kupffer cells, sinusoidal endothelial cells, and hepatic stellate cells) are also thought to be components of the immunosuppressive microenvironment [27]. Based on this theoretical background, anti-VEGF therapies such as anti-VEGF antibodies and multikinase inhibitors that possess VEGF receptor inhibitory activity will (1) enhance the antigen presentation ability of DCs, (2) promote T-cell activation in the priming phase, (3) normalize tumor vasculature and thereby improve trafficking and infiltration of T-cells from the lymph nodes to the tumor, (4) convert an immunosuppressive tumor microenvironment into an immune-permissive one by downregulating Tregs, TAMs, and MDSCs (described earlier), thereby negatively regulating humoral factors such as TGF- and JTK2 IL-10 [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17] (Fig. ?(Fig.5),5), and, at this point, (5) facilitate the effect of anti-PD-1/PD-L1 therapy to enhance antitumor activity (Fig. ?(Fig.6).6). The combination of anti-VEGF and anti-PD-1/PD-L1 antibodies thus exerts the following four actions (4Rs) to restore an effective cancer-immunity cycle to attack the tumor (Fig. ?(Fig.6):6): (1) Recognizing effect: anti-VEGF inhibits VEGF-mediated suppression of DC maturation, thereby enabling efficient priming and activation of T-cell responses against tumor antigens [1, 2, 3, 4, 5, 6, 7]. (2) Recruitment effect: anti-VEGF normalizes tumor vasculature, resulting in increased infiltration of T-cells into the tumor [1, 7, 8, 9, 10, 11, 12, 13]. (3) Reprogramming effect: anti-VEGF decreases the activity of MDSCs, Tregs, and TAMs, thereby enabling reprogramming of the tumor microenvironment from immunosuppressive to immune-permissive [1, 7, 14, 15, 16, 17]. (4) Restoring effect: the ability of immune checkpoint inhibitors (ICIs) to restore anticancer immunity through T-cell-mediated cancer cell killing is further enhanced by anti-VEGF-mediated immunomodulatory effects [7, 18, 19, 20]. This results in the fragmentation of proteins in necrotic tumor cells and the subsequent generation of cancer antigenic peptides. These antigens are recognized by DCs and presented as antigens by MHC class I molecules, further promoting the cancer-immunity.

Open in another window Scientific Rationale for Combination Immunotherapy with PD-1/PD-L1 Antibody plus Anti-VEGF/Molecular Targeted Agent High levels of vascular endothelial growth factor (VEGF) released from hypoxic tumor cells and the vascular endothelium induce angiogenesis, thereby contributing to proliferation, invasion, and metastasis of cancer cells