Targeting the innate immunoreceptor RIG-I overcomes melanoma-intrinsic resistance to T cell immunotherapy

Such, Lina; Zhao, Fang; Liu, Derek; Thier, Beatrice; Le‐Trilling, Vu Thuy Khanh; Sucker, Antje; Coch, Christoph; Pieper, Natalia; Howe, Sebastian; Bhat, Hilal; Kalkavan, Halime; Ritter, Cathrin; Brinkhaus, Robin; Ugurel, Selma; Köster, Johannes; Seifert, Ulrike; Dittmer, Ulf; Schüler, Martin; Lang, Karl S.; Kufer, Thomas A.; Hartmann, Gunther; Becker, Jürgen C.; Horn, Susanne; Ferrone, Soldano; Liu, David; Allen, Eliezer M. Van; Schadendorf, Dirk; Griewank, Klaus G.; Trilling, Mirko; Paschen, Annette

doi:10.1172/jci131572

Cited by 39 publications

(42 citation statements)

References 64 publications

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“…Recently, the anti-TIGIT therapeutics have drawn great attention in treating colorectal cancer, breast cancer, and melanoma through modulating the activities of CD8 + T, T-reg, and NK cells 61 . Blockage of CD112R and TIGIT signaling sensitizes human natural killer cell cytotoxicity functions on melanoma 62 . The OS T-reg cells expressed the canonical gene signature including the FOXP3 and IL2RA (Fig.…”

Section: Resultsmentioning

confidence: 99%

Single-cell RNA landscape of intratumoral heterogeneity and immunosuppressive microenvironment in advanced osteosarcoma

et al. 2020

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Osteosarcoma is the most frequent primary bone tumor with poor prognosis. Through RNA-sequencing of 100,987 individual cells from 7 primary, 2 recurrent, and 2 lung metastatic osteosarcoma lesions, 11 major cell clusters are identified based on unbiased clustering of gene expression profiles and canonical markers. The transcriptomic properties, regulators and dynamics of osteosarcoma malignant cells together with their tumor microenvironment particularly stromal and immune cells are characterized. The transdifferentiation of malignant osteoblastic cells from malignant chondroblastic cells is revealed by analyses of inferred copy-number variation and trajectory. A proinflammatory FABP4+ macrophages infiltration is noticed in lung metastatic osteosarcoma lesions. Lower osteoclasts infiltration is observed in chondroblastic, recurrent and lung metastatic osteosarcoma lesions compared to primary osteoblastic osteosarcoma lesions. Importantly, TIGIT blockade enhances the cytotoxicity effects of the primary CD3+ T cells with high proportion of TIGIT+ cells against osteosarcoma. These results present a single-cell atlas, explore intratumor heterogeneity, and provide potential therapeutic targets for osteosarcoma.

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Section: Resultsmentioning

confidence: 99%

Single-cell RNA landscape of intratumoral heterogeneity and immunosuppressive microenvironment in advanced osteosarcoma

et al. 2020

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“…NK cell-based therapy might be an effective way to overcome this type of resistance, for the MHC-I loss is an activating signal for NK cell toxicity ( 144 ). RIG-I activation is also a promising strategy ( 145 ). Kalbasi et al.…”

Section: Potential Strategies To Overcome Armentioning

confidence: 99%

Acquired Resistance to Immune Checkpoint Blockades: The Underlying Mechanisms and Potential Strategies

et al. 2021

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The immune checkpoint blockade therapy has completely transformed cancer treatment modalities because of its unprecedented and durable clinical responses in various cancers. With the increasing use of immune checkpoint blockades in clinical practice, a large number of patients develop acquired resistance. However, the knowledge about acquired resistance to immune checkpoint blockades is limited and poorly summarized. In this review, we clarify the principal elements of acquired resistance to immune checkpoint blockades. The definition of acquired resistance is heterogeneous among groups or societies, but the expert consensus of The Society for Immunotherapy of Cancer can be referred. Oligo-progression is the main pattern of acquired resistance. Acquired resistance can be derived from the selection of resistant cancer cell clones that exist in the tumor mass before therapeutic intervention or gradual acquisition in the sensitive cancer cells. Specifically, tumor intrinsic mechanisms include neoantigen depletion, defects in antigen presentation machinery, aberrations of interferon signaling, tumor-induced exclusion/immunosuppression, and tumor cell plasticity. Tumor extrinsic mechanisms include upregulation of other immune checkpoints. Presently, a set of treatment modalities is applied to patients with similar clinical characteristics or resistance mechanisms for overcoming acquired resistance, and hence, further research is required.

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“…Similarly, truncation in the β2-microglobulin gene resulting in defects in MHC-I-mediated antigen presentation and loss-of-function mutations to JAK1 or JAK2, implying defects to the transduction of antiviral IFN signals; mediate resistance to PD-1 blockade in melanoma [ 135 ]. Given that immunostimulatory roles for PRRs have been identified in immunotherapy settings [ 136 , 137 , 138 , 139 , 140 ], they may also be targeted in acquired resistance to this form of therapy, with profound implications to the susceptibility of such edited tumors to OVs. Together, these studies show how escape from immune pressure, in the context of immunoediting in the course of tumor progression, or in the context of immunotherapy; can directly contribute to reduced resistance to infection of cancer cells with OVs.…”

Section: Immunoediting Selects For Cancer Cells With Defects In Immentioning

confidence: 99%

Oncolytic Virotherapy: The Cancer Cell Side

Ehrlich

Bacharach

2021

Cancers

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Cell autonomous immunity genes mediate the multiple stages of anti-viral defenses, including recognition of invading pathogens, inhibition of viral replication, reprogramming of cellular metabolism, programmed-cell-death, paracrine induction of antiviral state, and activation of immunostimulatory inflammation. In tumor development and/or immunotherapy settings, selective pressure applied by the immune system results in tumor immunoediting, a reduction in the immunostimulatory potential of the cancer cell. This editing process comprises the reduced expression and/or function of cell autonomous immunity genes, allowing for immune-evasion of the tumor while concomitantly attenuating anti-viral defenses. Combined with the oncogene-enhanced anabolic nature of cancer-cell metabolism, this attenuation of antiviral defenses contributes to viral replication and to the selectivity of oncolytic viruses (OVs) towards malignant cells. Here, we review the manners by which oncogene-mediated transformation and tumor immunoediting combine to alter the intracellular milieu of tumor cells, for the benefit of OV replication. We also explore the functional connection between oncogenic signaling and epigenetic silencing, and the way by which restriction of such silencing results in immune activation. Together, the picture that emerges is one in which OVs and epigenetic modifiers are part of a growing therapeutic toolbox that employs activation of anti-tumor immunity for cancer therapy.

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Targeting the innate immunoreceptor RIG-I overcomes melanoma-intrinsic resistance to T cell immunotherapy

Cited by 39 publications

References 64 publications

Single-cell RNA landscape of intratumoral heterogeneity and immunosuppressive microenvironment in advanced osteosarcoma

Single-cell RNA landscape of intratumoral heterogeneity and immunosuppressive microenvironment in advanced osteosarcoma

Acquired Resistance to Immune Checkpoint Blockades: The Underlying Mechanisms and Potential Strategies

Oncolytic Virotherapy: The Cancer Cell Side

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