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

Ganesh, Shanthi; Shui, Xue; Craig, Kevin; Park, Jihye; Wang, Weimin; Brown, Bob D.; Abrams, Marc

doi:10.1016/j.ymthe.2018.09.005

Cited by 85 publications

(67 citation statements)

References 79 publications

(115 reference statements)

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“…Although the above studies of tumor-intrinsic WNT/b-catenin signaling have been evaluated in the context of melanoma, the impact of this pathway in driving the non-T-cell-inflamed tumor microenvironment in other tumor types are increasingly being recognized. In syngeneic murine models of B16F10 melanoma, 4T1 mammary carcinoma, Neuro2A neuroblastoma, and Renca renal adenocarcinoma, blocking b-catenin pathway signaling via RNA interference resulted in influx of CD8 þ T cells and increase in IFNgassociated gene targets (13). Subsequent combination with immunotherapy yielded complete regressions in the majority of treated animals.…”

Section: Introductionmentioning

confidence: 99%

WNT/β-catenin Pathway Activation Correlates with Immune Exclusion across Human Cancers

Luke

Bao

Sweis

et al. 2019

Clinical Cancer Research

472

392

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Purpose: The T-cell-inflamed phenotype correlates with efficacy of immune-checkpoint blockade, whereas non-Tcell-inflamed tumors infrequently benefit. Tumor-intrinsic WNT/b-catenin signaling mediates immune exclusion in melanoma, but association with the non-T-cell-inflamed tumor microenvironment in other tumor types is not well understood. Experimental Design: Using The Cancer Genome Atlas (TCGA), a T-cell-inflamed gene expression signature segregated samples within tumor types. Activation of WNT/b-catenin signaling was inferred using three approaches: somatic mutations or somatic copy number alterations (SCNA) in b-catenin signaling elements including CTNNB1, APC, APC2, AXIN1, and AXIN2; pathway prediction from RNA-sequencing gene expression; and inverse correlation of b-catenin protein levels with the T-cell-inflamed gene expression signature. Results: Across TCGA, 3,137/9,244 (33.9%) tumors were non-T-cell-inflamed, whereas 3,161/9,244 (34.2%) were T-cell-inflamed. Non-T-cell-inflamed tumors demonstrated significantly lower expression of T-cell inflammation genes relative to matched normal tissue, arguing for loss of a natural immune phenotype. Mutations of b-catenin signaling molecules in non-T-cell-inflamed tumors were enriched threefold relative to T-cell-inflamed tumors. Across 31 tumors, 28 (90%) demonstrated activated b-catenin signaling in the non-T-cellinflamed subset by at least one method. This included target molecule expression from somatic mutations and/or SCNAs of b-catenin signaling elements (19 tumors, 61%), pathway analysis (14 tumors, 45%), and increased b-catenin protein levels (20 tumors, 65%). Conclusions: Activation of tumor-intrinsic WNT/b-catenin signaling is enriched in non-T-cell-inflamed tumors. These data provide a strong rationale for development of pharmacologic inhibitors of this pathway with the aim of restoring immune cell infiltration and augmenting immunotherapy. See related commentary by Dangaj et al., p. 2943

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Section: Introductionmentioning

confidence: 99%

WNT/β-catenin Pathway Activation Correlates with Immune Exclusion across Human Cancers

Luke

Bao

Sweis

et al. 2019

Clinical Cancer Research

472

392

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“…Similar observations were made upon pharmacologically blocking canonical Wnt signaling in tumor DCs (17, 23-25, 27, 48, 59). In contrast, Wnt-conditioned DCs or tumor DCs expressing a constitutively active form of β-catenin is less potent in capturing and cross-presenting TAAs (17,21,22,27,48). Collectively, these studies show that the activation of canonical Wnt signaling pathway in tumor DCs suppresses efficient capture of tumor-associated antigens and cross-priming of CD8 + T cells.…”

Section: Consequence Of Wnt Inhibitors Plus Tlr Vaccine Adjuvants On mentioning

confidence: 81%

“…Tumor growth, migration, and metastasis (43)(44)(45) Immune cell exclusion (17,27,28,(46)(47)(48) augmented DCs activation with an increased expression of costimulatory molecules and decreased expression of co-inhibitory molecules (21,22,56). Collectively, these studies show that Wnt/β-catenin signaling interferes with DC maturation and activation in the TME.…”

Section: Wnt Signaling In Tumor Cellsmentioning

confidence: 83%

“…In addition, XAV 939 in combination with vaccines enhances anti-tumor immune responses by potently activating DCs in mice (83). Similarly, RNAi-mediated inhibition of β-catenin resulted in marked increase in antitumor immune response with reduced tumor burden in models of B16F10 melanoma, 4T1 mammary carcinoma, Neuro2A neuroblastoma, and renal adenocarcinoma (48). Another potential approach to promote β-catenin degradation is by activating GSK3β (55).…”

Section: Promoting β-Catenin Degradationmentioning

confidence: 99%

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Wnt Signaling Cascade in Dendritic Cells and Regulation of Anti-tumor Immunity

et al. 2020

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Dendritic cells (DCs) control the strength and quality of antigen-specific adaptive immune responses. This is critical for launching a robust immunity against invading pathogens while maintaining a state of tolerance to self-antigens. However, this also represents a fundamental barrier to anti-tumor immune responses and cancer immunotherapy. DCs in the tumor microenvironment (TME) play a key role in this process. The factors in the TME and signaling networks that program DCs to a regulatory state are not fully understood. Recent advances point to novel mechanisms by which the canonical Wnt signaling cascade in DCs regulates immune suppression, and the same pathway in tumors is associated with the evasion of anti-tumor immunity. Here, we review these recent advances in the context of the pleiotropic effects of the Wnts in shaping anti-tumor immune responses by modulating DC functions. In addition, we will discuss how Wnt/β-catenin pathway in DCs can be targeted for successful cancer immunotherapy.Keywords: Wnt, dendritic cells, beta-catenin (β-catenin), tumor microenvironment (TME), immunotherapy, anti-tumor immunity, immunotherapy immunotherapies against a whole range of human cancers.

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“…Combined application of inhibitors of the WNT/β‐catenin signaling pathway with immunocheckpoint blockers may be a more effective clinical treatment for sensitive cancers. The combination of PD‐1 antibody and biological nanoparticles of β‐catenin siRNA has been effective in animal experiments, providing an effective strategy for clinical cancer treatment 159,160 …”

Section: Abnormal Signaling Pathway Transduction and Related Protein mentioning

confidence: 99%

Study and analysis of antitumor resistance mechanism of PD1/PD‐L1 immune checkpoint blocker

Wang

2020

Cancer Medicine

100

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Immunocheckpoint proteins of tumor infiltrating lymphocytes play an important role in tumor prognosis in the course of tumor clinicopathology. PD‐1 (Programmed cell death protein 1) is an important immunosuppressive molecule. By binding to PD‐L1 (programmed cell death‐ligand 1), it blocks TCR and its costimulus signal transduction, inhibits the activation and proliferation of T cells, depletes the function of effector T cells, and enables tumor cells to achieve immune escape. In recent years, immunocheckpoint blocking therapy targeting the PD‐1/PD‐L1 axis has achieved good results in a variety of malignant tumors, pushing tumor immunotherapy to a new milestone, such as anti‐PD‐1 monoclonal antibody Nivolumab, Pembrolizumab, and anti‐PD‐L1 monoclonal antibody Atezolizumab, which are considered as potential antitumor drugs. It was found in clinical use that some patients obtained long‐term efficacy, but most of them developed drug resistance recurrence in the later stage. The high incidence of drug resistance (including primary and acquired drug resistance) still cannot be ignored, which limited its clinical application and became a new problem in this field. Due to tumor heterogeneity, current limited research shows that PD‐1 or PD‐L1 monoclonal antibody drug resistance may be related to the following factors: mutation of tumor antigen and antigen presentation process, multiple immune checkpoint interactions, immune microenvironment changes dynamically, activation of oncogenic pathways, gene mutation and epigenetic changes of key proteins in tumors, tumor competitive metabolism, and accumulation of metabolites, etc, mechanisms of resistance are complex. Therefore, it is the most urgent task to further elucidate the mechanism of immune checkpoint inhibitor resistance, discover multitumor universal biomarkers, and develop new target agents to improve the response rate of immunotherapy in patients. In this study, the mechanism of anti‐PD‐1/PD‐L1 drug resistance in tumors, the potential biomarkers for predicting PD‐1 acquired resistance, and the recent development of combination therapy were reviewed one by one. It is believed that, based on the complex mechanism of drug resistance, it is of no clinical significance to simply search for and regulate drug resistance targets, and it may even produce drug resistance again soon. It is speculated that according to the possible tumor characteristics, three types of treatment methods should be combined to change the tumor microenvironment ecology and eliminate various heterogeneous tumor subsets, so as to reduce tumor drug resistance and improve long‐term clinical efficacy.

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

Cited by 85 publications

References 79 publications

WNT/β-catenin Pathway Activation Correlates with Immune Exclusion across Human Cancers

WNT/β-catenin Pathway Activation Correlates with Immune Exclusion across Human Cancers

Wnt Signaling Cascade in Dendritic Cells and Regulation of Anti-tumor Immunity

Study and analysis of antitumor resistance mechanism of PD1/PD‐L1 immune checkpoint blocker

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