Predicting the response to CTLA-4 blockade by longitudinal noninvasive monitoring of CD8 T cells

Rashidian, Mohammad; Ingram, Jessica R.; Dougan, Michael; Dongre, Anushka; Whang, Katherine A.; LeGall, Camille; Cragnolini, Juan J.; Bierie, Brian; Gostissa, Monica; Gorman, James R.; Grotenbreg, Gijsbert M.; Bhan, Atul K.; Weinberg, Robert A.; Ploegh, Hidde L.

doi:10.1084/jem.20161950

Cited by 203 publications

(283 citation statements)

References 43 publications

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“…Not-surprisingly, stronger infiltration of CD8 + T cells into tumors generally associates with better prognosis; this has been demonstrated in various cancer types such as melanoma (2,3), ovarian (4), colorectal (5), bladder (6), breast (7), and pancreatic (8) cancer. Furthermore, stronger infiltration of CD8 + T cells can predict patient response to standard of care chemotherapy (9)(10)(11) and to immune checkpoint blockade therapy such as anti-CTLA-4 (12) or anti-PD-1 (13,14). Therefore, it is important to characterize the infiltration of CD8 + T cells in solid tumors and mechanisms that regulate this.…”

mentioning

confidence: 99%

Infiltration of CD8⁺ T cells into tumor-cell clusters in Triple Negative Breast Cancer

Gruosso

Zuo

et al. 2018

Preprint

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Infiltration of CD8 + T lymphocytes into solid tumors is associated with good prognosis in various types of cancer, including Triple Negative Breast Cancers (TNBC). However, the mechanisms underlying different infiltration-levels are largely unknown. Here, we have characterized the spatial profile of CD8 + T cells around tumor-cell clusters in the core and margin regions in TNBC. Combining mathematical modeling and data analysis, we propose that there exists a possible chemo-repellent inside tumor-cell clusters, which prevents CD8 + T cells from infiltrating into tumor-cell clusters. Furthermore, investigation into the properties of collagen fibers suggests that variations in desmoplastic elements does not limit infiltration of CD8 + T lymphocytes into tumor-cell clusters. This is consistent with the prediction of our mathematical modeling analysis whereby CD8 + T cells are predicted to infiltrate the fibrotic barrier and their infiltration into tumor clusters is governed by other mechanisms involving a local repellent.tumor-infiltrating lymphocytes | tumor-cell clusters | extra-cellular matrix | triple-negative breast cancer X.L.

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mentioning

confidence: 99%

Infiltration of CD8⁺ T cells into tumor-cell clusters in Triple Negative Breast Cancer

Gruosso

Zuo

et al. 2018

Preprint

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“…The application of molecular imaging in immuno‐oncology is related to employing radiolabeled antibodies, antibodies fragments, peptides, and proteins to track immune checkpoint targets at the cellular and molecular levels and to uncover the dynamic changes of the biomarkers expression . Preclinical studies showed that immuno‐PET monitoring of CD8+ T cells could serve as a predictive and prognostic biomarker for immune checkpoint therapy . Currently, effective efforts are underway to define PD‐L1 or PD‐1 expression using noninvasive molecular probes, of which a large number of studies focused on the feasibility of antibody‐based tracers in immunotherapy …”

Section: Imaging Biomarkers For Immune Checkpoint Therapymentioning

confidence: 99%

“…70 Preclinical studies showed that immuno-PET monitoring of CD8+ T cells could serve as a predictive and prognostic biomarker for immune checkpoint therapy. 71,72 Currently, effective efforts are underway to define PD-L1 or PD-1 expression using noninvasive molecular probes, of which a large number of studies focused on the feasibility of antibody-based tracers in immunotherapy. [73][74][75][76][77][78][79][80][81][82] For PET/CT-based molecular imaging, 64 Cu and 89 Zr are the most common radionuclides used in immuno-oncology.…”

Section: Molecular Imagingmentioning

confidence: 99%

Role of medical imaging for immune checkpoint blockade therapy: From response assessment to prognosis prediction

2019

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Immune checkpoint blockade (ICB) represents a promising approach in cancer therapy. Owing to the peculiar biologic mechanisms of anticancer activity, checkpoint blockers are accompanied with distinctive response patterns and toxicity profiles. Medical imaging is the cornerstone for response assessment to immunotherapy and plays a critical role in monitoring of immune‐related adverse events (irAEs). Imaging‐based biomarkers have shown tremendous potential for the prediction of therapeutic efficacies and clinical outcomes in patients treated with checkpoint inhibitors. In this article, the landscape of current response assessment systems for immunotherapy was reviewed with a special focus on the latest advances in the assessment of responses to ICB. Emerging imaging biomarkers were discussed along with the challenges regarding their clinical transformation. In addition, the biological mechanisms and clinical applications of ICB and irAEs were also within the scope of this review.

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“…OT-I T cells tagged with fluorescently labeled anti-CD8 nanobodies were co-cultured for 4 hours in the presence of antigenic peptide-loaded syngeneic wild-type bone-marrow derived dendritic cells generated from B6 bone marrow (Rashidian et al, 2017;Inaba et al, 1992). The cells were fixed, stained and imaged using confocal microscopy as previously described (Kumari et al, 2015).…”

Section: Microscopy and Image Analysismentioning

confidence: 99%

DOCK2 sets the threshold for entry into the virtual memory CD8⁺T cell compartment by negatively regulating tonic TCR triggering

Demissie

Mahajan

Alsufyani

et al. 2019

Preprint

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The control of cytoskeletal dynamics by Dedicator of cytokinesis 2 (DOCK2), a hematopoietic cell-specific actin effector protein, has been implicated in TCR signaling and T cell migration. Biallelic mutations in Dock2 have been identified in patients with a recessive form of combined immunodeficiency with defects in T, B and NK cell activation. Surprisingly, we show here that certain immune functions of CD8 + T cells are enhanced in the absence of DOCK2. Dock2-deficient mice have a pronounced expansion of their memory T cell compartment. Bone marrow chimera and adoptive transfer studies indicate that these memory T cells develop in a cell-intrinsic manner following thymic egress. Transcriptional profiling, TCR repertoire analyses and cell surface marker expression indicate that Dock2-deficient naive CD8 + T cells directly convert into virtual memory cells without clonal effector T cell expansion. This direct conversion to memory is associated with a selective increase in TCR sensitivity to selfpeptide MHC in vivo and an enhanced response to weak agonist peptides ex vivo. In contrast, the response to strong agonist peptides remains unaltered in Dock2-deficient T cells. Collectively, these findings suggest that the regulation of the actin dynamics by DOCK2 enhances the threshold for entry into the virtual memory compartment by negatively regulating tonic TCR triggering in response to weak agonists.

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Predicting the response to CTLA-4 blockade by longitudinal noninvasive monitoring of CD8 T cells

Abstract: Rashidian et al. show that 89Zr-PEGylated single-domain antibodies that target CD8+ T cells can be used to monitor and evaluate the response to immunotherapy as a predictive tool.

Cited by 203 publications

References 43 publications

Infiltration of CD8⁺ T cells into tumor-cell clusters in Triple Negative Breast Cancer

Infiltration of CD8⁺ T cells into tumor-cell clusters in Triple Negative Breast Cancer

Role of medical imaging for immune checkpoint blockade therapy: From response assessment to prognosis prediction

DOCK2 sets the threshold for entry into the virtual memory CD8⁺T cell compartment by negatively regulating tonic TCR triggering

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Predicting the response to CTLA-4 blockade by longitudinal noninvasive monitoring of CD8 T cells

Abstract: Rashidian et al. show that 89Zr-PEGylated single-domain antibodies that target CD8+ T cells can be used to monitor and evaluate the response to immunotherapy as a predictive tool.

Cited by 203 publications

References 43 publications

Infiltration of CD8+ T cells into tumor-cell clusters in Triple Negative Breast Cancer

Infiltration of CD8+ T cells into tumor-cell clusters in Triple Negative Breast Cancer

Role of medical imaging for immune checkpoint blockade therapy: From response assessment to prognosis prediction

DOCK2 sets the threshold for entry into the virtual memory CD8+T cell compartment by negatively regulating tonic TCR triggering

Contact Info

Product

Resources

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Infiltration of CD8⁺ T cells into tumor-cell clusters in Triple Negative Breast Cancer

Infiltration of CD8⁺ T cells into tumor-cell clusters in Triple Negative Breast Cancer

DOCK2 sets the threshold for entry into the virtual memory CD8⁺T cell compartment by negatively regulating tonic TCR triggering