Anti-PD-1 antibody significantly increases therapeutic efficacy of Listeria monocytogenes (Lm)-LLO immunotherapy

Abstract

BackgroundOne of the significant tumor immune escape mechanisms and substantial barrier for successful immunotherapy is tumor-mediated inhibition of immune response through cell-to-cell or receptor/ligand interactions. Programmed death receptor-1 (PD-1) interaction with its ligands, PD-L1 and PD-L2, is one of the important strategies that many tumors employ to escape immune surveillance. Upon PD-Ls binding to PD-1, T cell receptor (TCR) signaling is dampened, causing inhibition of proliferation, decreased cytokine production, anergy and/or apoptosis. Thus PD-Ls expression by tumor cells serves as a protective mechanism, leading to suppression of tumor-infiltrating lymphocytes in the tumor microenvironment. Lm-LLO immunotherapies have been shown to be therapeutically effective due to their ability to induce potent antigen-specific immune responses. However, it has been demonstrated that infection with Lm leads to up-regulation of PD-L1 on mouse immune cells that can inhibit effector T cells through PD-1/PD-L1 pathway.MethodsTherapeutic and immune efficacy of Listeria-based vaccine (Lm-LLO-E7) in combination with anti-PD-1 antibody was tested in E7 antigen expressing TC-1 mouse tumor model. Tumor growth, survival, as well as peripheral and tumor-infiltrating immune cell profiles after immunotherapy were assessed.ResultsHere we demonstrate that the combination of an Lm-LLO immunotherapy with anti-PD-1 antibody that blocks PD-1/PD-L1 interaction, significantly improves immune and therapeutic efficacy of treatment in TC-1 mouse tumor model. Importantly, we show that in addition to significant reduction of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC) in both spleen and tumor microenvironment that are mediated solely by the Lm-LLO immunotherapy, the addition of anti-PD-1 antibody to the treatment results in significant increase of antigen-specific immune responses in periphery and CD8 T cell infiltration into the tumor. As a result, this combinational treatment leads to significant inhibition of tumor growth and prolonged survival/complete regression of tumors in treated animals.We also demonstrate that in vitro infection with Lm results in significant upregulation of surface PD-L1 expression on human monocyte-derived dendritic cells suggesting the translational capacity of this finding.ConclusionsOur findings demonstrate that combination of Lm-LLO-based vaccine with blocking of PD-1/PD-L1 interaction is a feasible approach with clinical translation potential that can lead to overall enhancement of the efficacy of anti-tumor immunotherapy.

A novel dendritic cell targeting HPV16 E7 synthetic vaccine in combination with PD-L1 blockade elicits therapeutic antitumor immunity in mice

“…To achieve the goal of in vivo DC targeted antigen delivery, the HPV16 E7 long peptide (amino acid [43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62] containing the dominant T cell epitopes was fused to the single-chain fragment variable (scFv) specific for DEC-205 (aDEC205) using a protein assembly strategy based on the SpyCatcher-SpyTag system as described previously. 26 The SpyTag was genetically fused to the C-terminus of aDEC205 to obtain aDEC205-SpyTag and the E7 long peptide was added to the C-terminus of SpyCatcherDN to obtain Sc-E7, respectively (Fig.…”

“…26 7 d later, the DLNs from the immunized mice were isolated and digested into single-cell suspensions, and then stimulated with 5 mg/mL E7 [49][50][51][52][53][54][55][56][57] peptide in a U-bottom 96-well plate for 6 h. The IFNg producing CD8 C T cells were then determined and analyzed by intracellular staining and flow cytometry. As shown in Fig.…”

The importance of correctly timing cancer immunotherapy

“…Furthermore, analysis of PBMCs following administration of a glypcian-3 (GPC3) peptide vaccine in advanced or metastatic HCC revealed a high expression of PD-1 on peptide-specific CD8 + T-cells [84]. Similarly, immunotherapy using Listeria monocytogenes (Lm)-LLO can be improved by reduction of the Tregs and MDSCs, but as it is also associated with the upregulation of PD-L1 on immune cells, in particular macrophages, the use of antibodies blocking the PD-1:PD-L1 axis is justified [85]. Indeed, administration of the PD-1 blocking antibody in combination with the cancer vaccine caused increased tumor regression.…”

Antigen-Specific Antitumor Responses Induced by OX40 Agonist Are Enhanced by the IDO Inhibitor Indoximod

“…We and others have previously demonstrated that successful cancer immunotherapy requires simultaneous targeting of both effector and suppressor arms of the immune system (41)(42)(43)(44)(45). Because OX40 leads to increased INFg expression in the periphery and within the tumor microenvironment (16,17) and INFg promotes the induction of IDO, we hypothesized that OX40-based antitumor immunotherapy could be improved by reducing immune suppression through inhibition of IDO.…”