Spatial computation of intratumoral T cells correlates with survival of patients with pancreatic cancer

Carstens, Julienne L.; Sampaio, Pedro Corrêa de; Yang, Dalu; Barua, Souptik; Wang, Huamin; Rao, Arvind; Allison, James P.; LeBleu, Valerie S.; Kalluri, Raghu

doi:10.1038/ncomms15095

Cited by 507 publications

(515 citation statements)

References 39 publications

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“…Random integration of sequential Abs within a multiplex panel may lead to imbalanced signals, incomplete staining through interference with previously applied tyramide signal amplification (TSA), disruption of epitopes, and removal of TSA fluorophores because of repetitive antigen-retrievals at high temperature 80,81 . Therefore, each Ab was tested individually for its optimal position in the sequence of multiplex staining to minimize interference with previous Ab-TSA complexes or by alteration of epitopes.…”

Section: Pathway Analysismentioning

confidence: 99%

“…Multiplexed slides were scanned on a Vectra Multispectral Imaging System version 2 (Perkin Elmer) as described 80,81 . Briefly, a spectral library from spectral peaks emitted by each fluorophore from single stained slides was created with the inform Advanced Image Analysis software (InForm 2.4, PerkinElmer) and used for spectral unmixing of multispectral images allowing for identification of all markers of interest.…”

Section: Tissue Imaging Spectral Unmixing and Phenotypingmentioning

confidence: 99%

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B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma

Griss

Bauer

Wagner

et al. 2018

Preprint

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Tumor associated inflammation predicts response to immune checkpoint blockade in human melanoma. Established mechanisms that underlie therapy response and resistance center on anti-tumor T cell responses.Here we show that tumor-associated B cells are vital to tumor associated inflammation.Autologous B cells were directly induced by melanoma conditioned medium, expressed proand anti-inflammatory factors, and differentiated towards a plasmablast-like phenotype in vitro .We could identify this phenotype as a distinct cluster of B cells in an independent public single-cell RNA-seq dataset from melanoma tumors. There, plasmablast-like tumor-associated B cells showed expression of CD8+T cell-recruiting chemokines such as CCL3, CCL4, CCL5 and CCL28. Depletion of tumor associated B cells in metastatic melanoma patients by anti-CD20 immunotherapy decreased overall inflammation and CD8+T cell numbers in the human melanoma TME. Conversely, the frequency of plasmablast-like B cells in pretherapy melanoma samples predicted response and survival to immune checkpoint blockade in two independent cohorts. Tumor-associated B cells therefore orchestrate and sustain tumor inflammation, recruit CD8+ T effector cells and may represent a predictor for response and survival to immune checkpoint blockade in human melanoma.2 Cancers such as melanoma, lung, and kidney cancer often present with an inflamed but immunosuppressive tumor microenvironment (TME). Immune checkpoint blocking (ICB) antibodies have significantly improved cancer therapy by overcoming inhibition of T cell effector functions. Yet, a considerable number of patients does not benefit from ICB therapy 1 . It is therefore key to understand the mechanisms that regulate inflammation within the TME to develop novel therapies and improve patient survival. B cells promote both acute immune-associated inflammation for protection against foreign pathogens as well as chronic inflammation in autoimmune diseases and persistent infection. Mouse cancer models show that tumor-associated B cells (TAB) promote tumor inflammation 2,3 but may also inhibit anti-tumor T cell-dependent therapy responses 4-7 . The immuno-inhibitory function of TAB in these models resembles that of regulatory B cells (Breg), which are an established source of inhibitory cytokines such as IL-10 and TGF-b (reviewed in 8 ). In human cancer, Breg were described by either phenotyping, direct detection of immunoinhibitory cytokines or surface molecules, and/or immunosuppressive function 4,[9][10][11][12][13] .Often Breg frequencies increase with tumor progression and are enriched in tumors compared to peripheral blood or adjacent normal tissue. Increased IL-10 + B cell numbers can also be accompanied by increased numbers of CD4 + CD25 +/high CD127 low/and Foxp3 + Tregs in tumor tissues 10,12,14,15 which were independently associated with tumor progression or reduced patient survival.In human melanoma, up to 33% of the immune cells can be TAB 16,17 and phenotypic analysis has revealed CD20+ TAB (reviewed in 18 ) and CD1...

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Section: Pathway Analysismentioning

confidence: 99%

Section: Tissue Imaging Spectral Unmixing and Phenotypingmentioning

confidence: 99%

B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma

Griss

Bauer

Wagner

et al. 2018

Preprint

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“…With this respect, it is of great importance to consider the spatiotemporal dynamics of different immune cell types that infiltrate into tumors . Spatial distribution of cytotoxic T cells in proximity to cancer cells has just recently been demonstrated to correlate with increased overall survival of patients with pancreatic cancer . Like the dynamics of immune reaction against tumors, infiltration of immune cells into tumors takes place .…”

Section: Immunological Basis For Design Of Multimodal Radio‐immunothementioning

confidence: 99%

“…130 Spatial distribution of cytotoxic T cells in proximity to cancer cells has just recently been demonstrated to correlate with increased overall survival of patients with pancreatic cancer. 131 Like the dynamics of immune reaction against tumors, 132 infiltration of immune cells into tumors takes place. 133 Hettich and colleagues demonstrated that irradiation with 2×12 Gy on consecutive days of B16 melanoma tumors induces a high infiltration of CD8+ T cells at day 5 after the last irradiation.…”

Section: Dynamics Of Immune Cell Infiltrationmentioning

confidence: 99%

Immunomodulation by ionizing radiation—impact for design of radio‐immunotherapies and for treatment of inflammatory diseases

Frey

Rückert

Deloch

et al. 2017

Immunological Reviews

156

127

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Ionizing radiation is often regarded as an element of danger. But, danger responses on the cellular and molecular level are often beneficial with regard to the induction of anti-tumor immunity and for amelioration of inflammation. We outline how in dependence of radiation dose and fraction, radiation itself-and especially in combination with immune modulators-impacts on the innate and adaptive immune system. Focus is set on radiation-induced changes of the tumor cell phenotype and the cellular microenvironment including immunogenic cancer cell death. Mechanisms how anti-tumor immune responses are triggered by radiotherapy in combination with hyperthermia, inhibition of apoptosis, the adjuvant AnnexinA5, or vaccination with high hydrostatic pressure-killed autologous tumor cells are discussed. Building on this, feasible multimodal radio-immunotherapy concepts are reviewed including overcoming immune suppression by immune checkpoint inhibitors and by targeting TGF-β. Since radiation-induced tissue damage, inflammation, and anti-tumor immune responses are interconnected, the impact of lower doses of radiation on amelioration of inflammation is outlined. Closely meshed immune monitoring concepts based on the liquid biopsy blood are suggested for prognosis and prediction of cancer and non-cancer inflammatory diseases. Finally, challenges and visions for the design of cancer radio-immunotherapies and for treatment of benign inflammatory diseases are given.

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“…Visualizing spatial phenomena in tumors has predominantly been limited to protein expression, cell type, or a single geostatistical measure. [11][12][13][14][15] While these measures have been shown to have modest clinical utility, they do not readily provide insight into underlying biological processes. We hypothesize that jointly monitoring six geostatistics will enable visualization of spatial processes at both the global and local scale.…”

Section: Introductionmentioning

confidence: 99%

Geostatistical visualization of ecological interactions in tumors

Boyce

Mallick

2019

Preprint

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Recent advances in our understanding of cancer progression have highlighted the important role played by proteomic heterogeneity and the tumor microenvironment. Single-cell measurement technologies have enabled deep investigation of tumor heterogeneity. However, tools to visualize and interpret single-cell data have lagged behind experimental methods; currently, dimensionality reduction and clustering techniques, such as t-sne and SPADE, are the most prevalent visualization techniques. However, such techniques do not enable the visualization of the super-cellular structures that arise either via microenvironmental forces (e.g. hypoxia) or through cell-cell interactions. They additionally do not allow the visualization of ecological niches that are critical to understanding tumor behavior. The advent of novel experimental hyperplex immunostaining platforms, capable of measuring the in situ protein expression of dozens of proteins simultaneously, necessitates novel computational tools to quantify and visualize spatial patterns in the tumor microenvironment. Here, we introduce an approach to visualize tumor heterogeneity that integrates multiple geostatistics to capture both global and local spatial patterns. We assess the utility of this approach using an agent-based model of tumor growth under four ecological contexts; predation, mutualism, commensalism, and parasitism. Spatial patterns are visualized in real time as the models progress. This application introduces both an ecological framework for characterizing cellular interactions in cancer and novel way of quantifying and visualizing spatial patterns in cancer.

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Spatial computation of intratumoral T cells correlates with survival of patients with pancreatic cancer

Cited by 507 publications

References 39 publications

B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma

B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma

Immunomodulation by ionizing radiation—impact for design of radio‐immunotherapies and for treatment of inflammatory diseases

Geostatistical visualization of ecological interactions in tumors

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