scholarly journals GPR182 limits antitumor immunity via chemokine scavenging in mouse melanoma models

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Robert J. Torphy ◽  
Yi Sun ◽  
Ronggui Lin ◽  
Alayna Caffrey-Carr ◽  
Yuki Fujiwara ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Checkpoint ◽  
Antitumor Immunity ◽  
Cell Function ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Deficient Mice

AbstractFor many solid tumors, immune checkpoint blockade therapy has become first line treatment, yet a large proportion of patients with immunologically cold tumors do not benefit due to the paucity of tumor infiltrating lymphocytes. Here we show that the orphan G Protein-Coupled Receptor 182 (GPR182) contributes to immunotherapy resistance in cancer via scavenging chemokines that are important for lymphocyte recruitment to tumors. GPR182 is primarily upregulated in melanoma-associated lymphatic endothelial cells (LECs) during tumorigenesis, and this atypical chemokine receptor endocytoses chemokines promiscuously. In GPR182-deficient mice, T cell infiltration into transplanted melanomas increases, leading to enhanced effector T cell function and improved antitumor immunity. Ablation of GPR182 leads to increased intratumoral concentrations of multiple chemokines and thereby sensitizes poorly immunogenic tumors to immune checkpoint blockade and adoptive cellular therapies. CXCR3 blockade reverses the improved antitumor immunity and T cell infiltration characteristic of GPR182-deficient mice. Our study thus identifies GPR182 as an upstream regulator of the CXCL9/CXCL10/CXCR3 axis that limits antitumor immunity and as a potential therapeutic target in immunologically cold tumors.

scholarly journals Antitumor immunity is defective in T cell–specific microRNA-155–deficient mice and is rescued by immune checkpoint blockade

2017 ◽  
Vol 292 (45) ◽  
pp. 18530-18541 ◽  
Author(s):  
Thomas B. Huffaker ◽  
Soh-Hyun Lee ◽  
William W. Tang ◽  
Jared A. Wallace ◽  
Margaret Alexander ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Checkpoint ◽  
Antitumor Immunity ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Deficient Mice

scholarly journals RNAi-Mediated β-Catenin Inhibition Promotes T Cell Infiltration and Antitumor Activity in Combination with Immune Checkpoint Blockade

2018 ◽  
Vol 26 (11) ◽  
pp. 2567-2579 ◽  
Author(s):  
Shanthi Ganesh ◽  
Xue Shui ◽  
Kevin P. Craig ◽  
Jihye Park ◽  
Weimin Wang ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Activity ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Cell Infiltration ◽  
T Cell Infiltration

RNAi-mediated beta-catenin inhibition to promote T-cell infiltration and antitumor activity in combination with immune checkpoint blockade.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14608-e14608 ◽  
Author(s):  
Shanthi Ganesh ◽  
Serena Shui ◽  
Cheng Lai ◽  
Hank Dudek ◽  
Weimin Wang ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Granzyme B ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Cell Infiltration ◽  
Tumor Growth Inhibition ◽  
Beta Catenin ◽  
T Cell Infiltration

e14608 Background: Recent research suggests an important role for Wnt/β-catenin signaling in mediating cancer immune evasion and resistance to immune checkpoint therapy. The mechnism is believed to involve blocking of specific cytokines which trigger immune cell recruitment to the tumor, resulting in the phenomenon of T-cell exclusion and rendering the tumor to a non-inflamed state. Inhibition of β-catenin may be an effective strategy for increasing the low response rate to these effective medicines in numerous cancer populations. DCR-BCAT is an advanced preclinical development candidate that has a potent and specific chemically-optimized RNA interference (RNAi) trigger targeting CTNNB1, the gene that encodes β-catenin, formulated in a tumor-selective lipid nanoparticle. Methods: Syngeneic murine models and transgenic MMTV-Wnt1 mouse models were used in this study. In both cases, a sequential dose regimen was employed where, in each dosing cycle, animals received DCR-BCAT, followed by a combination of anti-PD-1 and anti-CTLA-4 on subsequent days. Pharmacodynamic endpoints included CTNNB1 (β-catenin), CCL4, PD-1, PD-L1 mRNA measurement by quantitative PCR, as well as β-catenin, perforin, and granzyme B immunohistochemistry. Results: In syngeneic models, β-catenin inhibition with DCR-BCAT significantly improved the T-cell infiltration. The combination of DCR-BCAT and immune checkpoint blockade yielded significant tumor growth inhibition compared to monotherapy in B16F10, 4T1, Neuro2A and Renca tumors. The combination therapy was associated with high levels of granzyme B and perforin, strongly suggesting that the mechanism of sensitization to checkpoint therapy was a sharp increase in T-cell mediated cytotoxicity. Finally, when DCR-BCAT was combined with anti-PD-1/CTLA-4 antibodies in mice which develop spontaneous Wnt-driven mammary tumors, checkpoint therapy potentiation yielded complete tumor regressions. Conclusions: These data offer proof-of-concept for conversion of non-inflamed tumors to inflamed tumors by β-catenin inhibition, and support clinical evaluation of this combination approach using a first-in-class RNAi-based agent.

scholarly journals Rethinking immune checkpoint blockade: ‘Beyond the T cell’

2021 ◽  
Vol 9 (1) ◽  
pp. e001460 ◽  
Author(s):  
Xiuting Liu ◽  
Graham D Hogg ◽  
David G DeNardo
Keyword(s):  
Immune System ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Antitumor Immunity ◽  
Checkpoint Inhibitors ◽  
Clinical Success ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

The clinical success of immune checkpoint inhibitors has highlighted the central role of the immune system in cancer control. Immune checkpoint inhibitors can reinvigorate anti-cancer immunity and are now the standard of care in a number of malignancies. However, research on immune checkpoint blockade has largely been framed with the central dogma that checkpoint therapies intrinsically target the T cell, triggering the tumoricidal potential of the adaptive immune system. Although T cells undoubtedly remain a critical piece of the story, mounting evidence, reviewed herein, indicates that much of the efficacy of checkpoint therapies may be attributable to the innate immune system. Emerging research suggests that T cell-directed checkpoint antibodies such as anti-programmed cell death protein-1 (PD-1) or programmed death-ligand-1 (PD-L1) can impact innate immunity by both direct and indirect pathways, which may ultimately shape clinical efficacy. However, the mechanisms and impacts of these activities have yet to be fully elucidated, and checkpoint therapies have potentially beneficial and detrimental effects on innate antitumor immunity. Further research into the role of innate subsets during checkpoint blockade may be critical for developing combination therapies to help overcome checkpoint resistance. The potential of checkpoint therapies to amplify innate antitumor immunity represents a promising new field that can be translated into innovative immunotherapies for patients fighting refractory malignancies.

scholarly journals B7-H5 blockade enhances CD8+ T-cell-mediated antitumor immunity in colorectal cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jiayu Wang ◽  
Hongya Wu ◽  
Yanjun Chen ◽  
Jinghan Zhu ◽  
Linqing Sun ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Inverse Correlation ◽  
Immune Checkpoint Blockade ◽  
Cell Infiltration ◽  
Tumor Immune Escape ◽  
T Cell Infiltration

AbstractNegative immune checkpoint blockade immunotherapy has shown potential for multiple malignancies including colorectal cancer (CRC). B7-H5, a novel negative immune checkpoint regulator, is highly expressed in tumor tissues and promotes tumor immune escape. However, the clinical significance of B7-H5 expression in CRC and the role of B7-H5 in the tumor microenvironment (TME) has not been fully clarified. In this study, we observed that high B7-H5 expression in CRC tissues was significantly correlated with the lymph node involvement, AJCC stage, and survival of CRC patients. A significant inverse correlation was also observed between B7-H5 expression and CD8+ T-cell infiltration in CRC tissues. Kaplan−Meier analysis showed that patients with high B7-H5 expression and low CD8+ T-cell infiltration had the worst prognosis in our cohort of CRC patients. Remarkably, both high B7-H5 expression and low CD8+ T infiltration were risk factors for overall survival. Additionally, B7-H5 blockade using a B7-H5 monoclonal antibody (B7-H5 mAb) effectively suppressed the growth of MC38 colon cancer tumors by enhancing the infiltration and Granzyme B production of CD8+ T cells. Importantly, the depletion of CD8+ T cells obviously abolished the antitumor effect of B7-H5 blockade in the MC38 tumors. In sum, our findings suggest that B7-H5 may be a valuably prognostic marker for CRC and a potential target for CRC immunotherapy.

scholarly journals IMMU-11. DUAL TARGETING OF IL-6 AND CD40 OVERCOMES GLIOBLASTOMA RESISTANCE TO IMMUNE CHECKPOINT BLOCKADE

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii107-ii107
Author(s):  
Fan Yang ◽  
Steven Brem ◽  
Yi Fan
Keyword(s):  
T Cell ◽  
Immune Checkpoint Blockade ◽  
Genetically Engineered ◽  
Checkpoint Blockade ◽  
Cell Infiltration ◽  
Genetic Ablation ◽  
T Cell Infiltration ◽  
Dual Targeting ◽  
Animal Survival ◽  
Cd40 Expression

Abstract Glioblastoma (GBM) is refractory to current T cell-based immunotherapies such as checkpoint blockade. GBM is characterized by extensive infiltration of immunosuppressive macrophages (Mφs) that contribute to the treatment resistance. Here we develop a dual-targeting strategy to synergistically activate tumor-associated Mφs, which overcomes GBM resistance to therapeutic blockade of the PD1 and CTLA4 checkpoints. Consistent with a previously established role of IL-6 in alternative Mφ polarization, we show that targeting IL-6 by genetic ablation or pharmacological inhibition moderately improves T cell infiltration and enhances animal survival in a genetically engineered mouse GBM model. However, IL-6 inhibition does not synergize PD-1 and CTLA-4 blockade in GBM. Interestingly, we reveal that anti-IL-6 therapy reduces CD40 expression in GBM-associated Mφs. Our transcriptome analysis identifies a Stat3/HIF-1a-mediated axis, through which IL-6 regulates CD40 expression in Mφs. Finally, we show that combination of IL-6 blockade with CD40 stimulation robustly reverses Mφ-mediated tumor immunosuppression, enhances T cell infiltration, and sensitizes GBM to PD-1 and CTLA-4 blockade treatment, cumulating in inhibited tumor growth and extended animal survival. These findings illustrate a cellular mechanism that regulates Mφ-mediated tumor immunity, and suggest that dual-targeting IL-6 and CD40 may offer exciting opportunities for improving immunotherapy against GBM.

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