Explaining the Paucity of Intratumoral T Cells: A Construction Out of Known Entities

Fearon, Douglas T.

doi:10.1101/sqb.2016.81.030783

Cited by 6 publications

(5 citation statements)

References 57 publications

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“…In contrast, anti-PD-1 alone had little impact on the production of cytokines from patient T cells. In keeping with our transcriptome data, multiplex immunoassays confirmed the consistent enrichment of immunoregulatory and chemoattractant cytokines including CXCL10 56,57 within the culture supernatants of T cells treated with avadomide alone or in combination with anti-PD-1 or anti-PD-L1 (including significantly increased CXCL10 production with combination therapy compared to avadomide alone) (Figure 5C). We next assessed the impact of treatment on T cell migration.…”

Section: Avadomide Induces An Inflammatory T Cell Secretome and Motilitysupporting

confidence: 82%

“…In contrast, predominantly type II IFNgassociated T cell responses have been reported for lenalidomide treatment, 72 that could reflect the reduced depth of Ikaros degradation induced by this immunomodulatory drug compared with avadomide. Our data using avadomide supports the concept of therapeutically reshaping noninflamed CLL and NHL tumors into T cell-inflamed TMEs, 22,56 that could engage both innate and adaptive immunity, to overcome resistance to checkpoint blockade. There is substantial evidence demonstrating that type I and II IFN signaling is required within TMEs to prevent development of an immunosuppressive state.…”

Section: Discussionsupporting

confidence: 68%

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Triggering interferon signaling in T cells with avadomide sensitizes CLL to anti-PD-L1/PD-1 immunotherapy

Ioannou

Hagner

Stokes

et al. 2021

Blood

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Cancer treatment has been transformed by checkpoint blockade therapies, with the highest anti-tumor activity of anti-programmed death 1 (PD-1) antibody therapy seen in Hodgkin lymphoma (HL). Disappointingly, response rates have been low in the non-Hodgkin lymphomas (NHLs), with no activity seen in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) with PD-1 blockade. Thus, identifying more powerful combination therapy is required for these patients. Here, we pre-clinically demonstrate enhanced anti-CLL activity following combinational therapy with anti-PD-1 or anti-PD-1 ligand (PD-L1) and avadomide, a cereblon E3 ligase modulator (CELMoD). Avadomide induced type I and II interferon (IFN) signaling in patient T cells, triggering a feedforward cascade of reinvigorated T cell responses. Immune modeling assays demonstrated that avadomide stimulated T cell activation, chemokine expression, motility and lytic synapses with CLL cells, as well as IFN-inducible feedback inhibition through upregulation of PD-L1. Patient-derived xenograft tumors treated with avadomide were converted to CD8+ T cell-inflamed tumor microenvironments (TMEs) that responded to anti-PD-L1/PD-1-based combination therapy. Notably, clinical analyses showed increased PD-L1 expression on T cells, as well as intratumoral expression of chemokine signaling genes in B cell malignancy patients receiving avadomide-based therapy. These data illustrate the importance of overcoming a low inflammatory T cell state to successfully sensitize CLL to checkpoint blockade-based combination therapy.

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Section: Avadomide Induces An Inflammatory T Cell Secretome and Motilitysupporting

confidence: 82%

Section: Discussionsupporting

confidence: 68%

Triggering interferon signaling in T cells with avadomide sensitizes CLL to anti-PD-L1/PD-1 immunotherapy

Ioannou

Hagner

Stokes

et al. 2021

Blood

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“…Thus, the immune-promoting T-CAF develops because these cells integrate signals from two T cell-produced cytokines to present a chemokine profile that could amplify the T cell-mediated immune reaction. Second, this study provides additional support to the concept that the regulation of T cell trafficking is another means by which tissues can determine whether they will be subject to immune-mediated damage (Buckley and McGettrick, 2018; Fearon, 2016; Groom and Luster, 2011a; Peske et al, 2015). The demonstration that the CAF may adopt not only a CXCL12 + /CXCL9 - chemokine profile that protects tumors, as previously shown, but also a CXCL12 - /CXCL9 + phenotype that has the capacity to promote immune attack emphasizes the various roles that stromal fibroblasts may adopt in immune-mediated damage to tissues, including auto-immunity.…”

Section: Resultssupporting

confidence: 54%

T cell-mediated development of stromal fibroblasts with an immune-enhancing chemokine profile

Yan

Fearon

2022

Preprint

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Stromal fibroblasts reside in inflammatory tissues that are characterized by either immune suppression or immune activation, but whether these cells adapt to these contrasting microenvironments is not known. Cancer-associated fibroblasts (CAFs) mediate immune quiescence by producing the chemokine CXCL12 that coats cancer cells to suppress T cell infiltration. We examined whether CAFs can adopt an immune-promoting chemokine profile. Single-cell RNA-sequencing of CAFs from mouse pancreatic adenocarcinomas identified a sub-population with decreased expression of CXCL12 and increased expression of the T cell-attracting chemokine, CXCL9, that was expanded when tumors were infiltrated with T cells. Conditioned media from activated CD8+ T cells containing TNFα and IFNγ converted the chemokine profile of stromal fibroblasts from a CXCL12+/CXCL9- immune suppressive phenotype into a CXCL12-/CXCL9+ immune-activating phenotype. Studies with recombinant cytokines showed that TNFα acted synergistically with IFNγ to induce CXCL9 expression, and alone was mainly responsible for suppressing CXCL12 expression. This coordinated chemokine switch demonstrates that stromal fibroblasts have a phenotypic plasticity that allow their adaptation to contrasting immune tissue microenvironments.

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“…While this observation is not yet mechanistically explained, the authors speculated that CXCR4 may act on T cells through cross-desensitization of other CKRs, such as CXCR3. Thus, CXCR4 antagonism is predicted to relieve inhibition of chemokine-mediated intratumoral recruitment mechanisms for T cells (114).…”

Section: Tumor-infiltrating Tregmentioning

confidence: 99%

Guidance factors orchestrating regulatory T cell positioning in tissues during development, homeostasis, and response

Mempel

Marangoni

2019

Immunological Reviews

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Over their lifetime, regulatory T cells (Treg) recalibrate their expression of trafficking receptors multiple times as they progress through development, respond to immune challenges, or adapt to the requirements of functioning in various non-lymphoid tissue (NLT) environments. These trafficking receptors, which include chemokine receptors (CKRs) and other G-protein coupled receptors (GPCRs), integrins, as well as selectins and their ligands, enable Treg not only to enter appropriate tissues from the bloodstream via post-capillary venules, but also to navigate these tissues to locally execute their immune-regulatory functions, and finally to seek out the right antigen-presenting cells and interact with these, in part in order to receive the signals that sustain their survival, proliferation, and functional activity, in part in order to execute their immunoregulatory function by altering APC function. Here, we will review our current knowledge of when and in what ways Treg alter their trafficking properties. We will focus on the chemokine system and try to identify specialized, non-redundant roles of individual receptors as well as similarities and differences to the conventional T cell compartment.

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Explaining the Paucity of Intratumoral T Cells: A Construction Out of Known Entities

Cited by 6 publications

References 57 publications

Triggering interferon signaling in T cells with avadomide sensitizes CLL to anti-PD-L1/PD-1 immunotherapy

Triggering interferon signaling in T cells with avadomide sensitizes CLL to anti-PD-L1/PD-1 immunotherapy

T cell-mediated development of stromal fibroblasts with an immune-enhancing chemokine profile

Guidance factors orchestrating regulatory T cell positioning in tissues during development, homeostasis, and response

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