Programmed cell death ligand 1 (PD-L1) blockade attenuates metastatic colon cancer growth in cAMP-response element-binding protein (CREB)-binding protein (CBP)/β-catenin inhibitor-treated livers

Osawa, Yosuke; Kojika, Ekumi; Nishikawa, Koji; Kimura, Maiko; Osakaya, Shigenori; Miyauchi, Hiromi; Kanto, Tatsuya; Kawakami, Yutaka; Kimura, Kiminori

doi:10.18632/oncotarget.26892

Cited by 14 publications

(9 citation statements)

References 29 publications

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“…Targeting CREB1 binding protein/β-catenin, combined with PD-1/PD-L1 blockade, has shown potential as a new therapeutic strategy for treating liver metastasis in CRC. 53 Further studies are needed on the role of CREB1 and TNF signaling in MSS cancers and their susceptibility to immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Reovirus sensitizes microsatellite stable colorectal cancer to anti-PD-1 treatment via cross-talk in innate and adaptive immune systems

Augustine

John

Friedman

et al. 2021

Preprint

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Background: Microsatellite stable (MSS) colorectal cancer (CRC) represents ~85% of all CRCs. These tumors are poorly immunogenic and largely resistant to immunotherapy, necessitating a need to develop new immune enhancing strategies. Oncolytic reovirus has a high propensity to replicate in KRAS mutant tumors which account for ~50% of MSS CRCs. Current study explores the ability of reovirus to potentiate the effect of immune checkpoint inhibition in MSS CRC. Methods: Effectiveness of reovirus infection was quantified through MTT assay for cell viability, and expression of immune-response genes by flow cytometry, RT-qPCR, and microarray. Computational analysis of differentially expressed genes was performed by TAC, DAVID and STRING. Combinatorial approach using anti-PD-1 monoclonal antibody was assessed in ex vivo and in vivo models. Live-cell imaging, tumor volume and survival were measured for quantification of anti-tumor activity. Expression of pattern recognition receptors (PRRs), cell surface and activation markers of immune cells, and PD-1/PD-L1 axis were studied using multi-color flow cytometry, immunoblotting, immunohistochemistry, and immunofluorescence. Results: Reovirus infection exerted growth arrest and expression of immune-response genes in CRCs cell lines in a KRAS-dependent manner. However, microsatellite instability, rather than KRAS status determined immune-repose pathways, functionalities and biological processes post-reovirus infection. Furthermore, reovirus significantly enhanced the anti-tumor activity of anti-human PD-1 [nivolumab] treatment in MSS CRC cell lines ex vivo. Similarly, reovirus increased the activity of anti-mouse PD-1 treatment in the CT26 [MSS, KRASMut], but not the MC38 [MSI, KRASWt] syngeneic mouse model of CRC. Combinatorial treatment has reduced the proliferative index, increased apoptosis and differentially altered PD-L1/PD-1 signaling among CT26 and MC38 tumors. Activation of innate immune system and expression of PRRs and antigen presentation markers were observed under reovirus and anti-PD-1 treatment that additionally reduced immunosuppressive macrophages. This led to an increase in T cell subsets, increase in effector T cell activation, and decrease in exhaustion markers specifically within CT26 microenvironment. Conclusion: The current study systematically evaluates immune characteristics and immune microenvironment of CRC under reovirus/anti-PD-1 combination treatment that proves increased effectiveness among MSS compared to MSI CRCs. This is a promising regimen warranting translation into clinical trials.

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Section: Discussionmentioning

confidence: 99%

Reovirus sensitizes microsatellite stable colorectal cancer to anti-PD-1 treatment via cross-talk in innate and adaptive immune systems

Augustine

John

Friedman

et al. 2021

Preprint

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“…We also quantified the Treg population by measuring co-expression of CD25 and FoxP3, but in contrast to other reports [ 14 , 35 ], we did not detect changes in the frequencies among treatment groups of this clearly detectable population that represented on average 3.5% of human TILs (Supplementary Fig 1 ). A previous report studying PRI-724, a CBP/β-catenin inhibitor, in a mouse model of colorectal cancer, observed increases in the Treg population with drug treatment, suggesting that a decrease in Tregs is not a consistent finding with β-catenin inhibition [ 37 ]. Our analysis of the myeloid populations showed that although they are underrepresented in general in humanized mice, we did observe substantial representation of these cells in tumors.…”

Section: Discussionmentioning

confidence: 99%

RX-5902, a novel β-catenin modulator, potentiates the efficacy of immune checkpoint inhibitors in preclinical models of triple-negative breast Cancer

et al. 2020

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Background Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited systemic treatment options. RX-5902 is a novel anti-cancer agent that inhibits phosphorylated-p68 and thus attenuates nuclear β-catenin signaling. The purpose of this study was to evaluate the ability of β-catenin signaling blockade to enhance the efficacy of anti-CTLA-4 and anti-PD-1 immune checkpoint blockade in immunocompetent, preclinical models of TNBC. Methods Treatment with RX-5902, anti-PD-1, anti-CTLA-4 or the combination was investigated in BALB/c mice injected with the 4 T1 TNBC cell line. Humanized BALB/c-Rag2nullIl2rγnullSIRPαNOD (hu-CB-BRGS) mice transplanted with a human immune system were implanted with MDA-MB-231 cells. Mice were randomized into treatment groups according to human hematopoietic chimerism and treated with RX-5902, anti-PD-1 or the combination. At sacrifice, bone marrow, lymph nodes, spleen and tumors were harvested for flow cytometry analysis of human immune cells. Results The addition of RX-5902 to CTLA-4 or PD-1 inhibitors resulted in decreased tumor growth in the 4 T1 and human immune system and MDA-MB-231 xenograft models. Immunologic analyses demonstrated a significant increase in the number of activated T cells in tumor infiltrating lymphocytes (TILs) with RX-5902 treatment compared to vehicle (p < 0.05). In the RX-5902/nivolumab combination group, there was a significant increase in the percentage of CD4+ T cells in TILs and increased systemic granzyme B production (p < 0.01). Conclusions Conclusions: RX-5902 enhanced the efficacy of nivolumab in a humanized, preclinical model of TNBC. Several changes in immunologic profiles were noted in mice treated with RX-5902 and the combination, including an increase in activated TILs and a decrease in human myeloid populations, that are often associated with immunosuppression in a tumor microenvironment. RX-5902 also was shown to potentiate the effects of checkpoint inhibitors of CTLA4 and the PD-1 inhibitor in the 4 T-1 murine TNBC model. These findings indicate that RX-5902 may have important immunomodulatory, as well as anti-tumor activity, in TNBC when combined with a checkpoint inhibitor.

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“…In addition, Cui et al has shown that ICG-001 effectively inhibited the metastatic progression of HCC tumors in both cell line and patient-derived xenograft mouse models [50]. Moreover, PRI-724, the derivative of ICG-001, was reported to induce CD8 + T-cells in ltrates and IFN-γ production in liver metastatic lesions in a mouse model of colon cancer with liver metastasis [51]. The combination treatment of anti-PD-L1 antibody and PRI-724 resulted in regression of tumor growth.…”

Section: Discussionmentioning

confidence: 99%

Wnt/β-catenin Inhibitor ICG-001 Enhances the Antitumor Efficacy of Radiotherapy by Increasing Radiation-induced DNA Damage and Improving Tumor Immune Microenvironment in Hepatocellular Carcinoma

Huang

Sheng

Xiao

et al. 2020

Preprint

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Background: Radiotherapy has a promising anti-tumor effect in hepatocellular carcinoma (HCC), depending on the its regulatory effects on both cancer cells and tumor immune microenvironment (TME). Wnt/β-catenin signaling pathway activation, which is one of the most common alterations in HCC patients, has been reported to induce radioresistance, and also create immunosuppressive TME. However, it is unclear whether inhibition of wnt/β-catenin pathway could enhance the treatment efficacy of radiotherapy. In this study, we aim to explore the effect of wnt/β-catenin inhibitor ICG-001 in combination with radiotherapy and the underlying mechanism in HCC.Methods: C57BL/6 and nude mouse subcutaneous tumor models were used to evaluate the efficacy of different treatment regimens in tumor growth control, tumor recurrence inhibition and survival improvement. Flow cytometry was performed to assess the alterations of tumor infiltrating lymphocytes (TILs). Radioresistance was investigated by clone formation assay and γ-H2AX measurements. Wnt/β-catenin and cGAS/STING pathway activation was detected by immunoblotting. Results: The addition of ICG-001 to radiotherapy exhibited better anti-tumor control efficacy in tumor-bearing C57BL/6 mice than nude mice, which suggested that ICG-001 had a critical role in activating TME. The comprehensive analysis of TILs revealed that compared with radiotherapy alone, the combination of ICG-001 with radiotherapy boosted the infiltration and IFN-γ production ability of TIL CD8+ T cells, meanwhile reduced the number of TIL Tregs. Moreover, mechanism study demonstrated that ICG-001 exerted a radiosensitizing effect on HCC cells, thus leading to stronger activation of cGAS/STING signaling pathway upon radiotherapy in vitro and in vivo. Utilization of STING inhibitor, C-176, significantly impaired the synergetic effect of ICG-001 with radiotherapy on tumor control and TME activation. Furthermore, combination therapy led to a stronger immunologic memory and lasting anti-tumor immunity than radiotherapy, thus preventing tumor relapse in HCC tumor-bearing mice.Conclusion: Our findings showed that ICG-001 increased radioresistance and improved TME upon radiotherapy in HCC. Compared with radiotherapy alone, the combination of ICG-001 with radiotherapy displayed better therapeutic efficacy in inhibiting tumor growth, prolonging survival, and preventing recurrence in tumor-bearing mice. These data indicated that ICG-001 might be a potential synergetic treatment for radiotherapy and radioimmunotherapy in HCC.

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Programmed cell death ligand 1 (PD-L1) blockade attenuates metastatic colon cancer growth in cAMP-response element-binding protein (CREB)-binding protein (CBP)/β-catenin inhibitor-treated livers

Cited by 14 publications

References 29 publications

Reovirus sensitizes microsatellite stable colorectal cancer to anti-PD-1 treatment via cross-talk in innate and adaptive immune systems

Reovirus sensitizes microsatellite stable colorectal cancer to anti-PD-1 treatment via cross-talk in innate and adaptive immune systems

RX-5902, a novel β-catenin modulator, potentiates the efficacy of immune checkpoint inhibitors in preclinical models of triple-negative breast Cancer

Wnt/β-catenin Inhibitor ICG-001 Enhances the Antitumor Efficacy of Radiotherapy by Increasing Radiation-induced DNA Damage and Improving Tumor Immune Microenvironment in Hepatocellular Carcinoma

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