Tumoral Immune Cell Exploitation in Colorectal Cancer Metastases Can Be Targeted Effectively by Anti-CCR5 Therapy in Cancer Patients

Halama, Niels; Zoernig, Inka; Berthel, Anna; Kahlert, Christoph; Klupp, Fee; Suarez-Carmona, Meggy; Suetterlin, Thomas; Brand, Karsten; Krauss, Juergen; Lasitschka, Felix; Lerchl, Tina; Luckner-Minden, Claudia; Ulrich, Alexis; Koch, Moritz; Weitz, Juergen; Schneider, Martin; Buechler, Markus W.; Zitvogel, Laurence; Herrmann, Thomas; Benner, Axel; Kunz, Christina; Luecke, Stephan; Springfeld, Christoph; Grabe, Niels; Falk, Christine S.; Jaeger, Dirk

doi:10.1016/j.ccell.2016.03.005

Cited by 419 publications

(379 citation statements)

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“…We performed histological staining for Ki67 (Dako M7240 antibody, 1:100), active caspase 3 (Abcam ab2302 antibody, 1:50), and CD3 (Leica Novocastra NCL-L-PS1 antibody, 1:50) on a Leica Bond automatic staining device using a hematoxylindiaminobenzidine (DAB) staining protocol as described previously (6,28). Stained whole slide tissue sections were digitized as described previously (6,28).…”

Section: Histological Assessmentmentioning

confidence: 99%

“…Stained whole slide tissue sections were digitized as described previously (6,28). On histological sections, we manually identified areas homogenously occupied by tumor cells or immune cells (in the tumor or around the tumor).…”

Section: Histological Assessmentmentioning

confidence: 99%

“…Additionally, many more drugs are currently investigated in clinical trials, especially combination therapies aiming at the stromal compartment (4,5). These approaches act on the complex interactions in the tumor microenvironment, as we could show recently in macrophage-targeted immunotherapies (6).…”

Section: Introductionmentioning

confidence: 95%

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In Silico Modeling of Immunotherapy and Stroma-Targeting Therapies in Human Colorectal Cancer

et al. 2017

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Despite the fact that the local immunological microenvironment shapes the prognosis of colorectal cancer, immunotherapy has shown no benefit for the vast majority of colorectal cancer patients. A better understanding of the complex immunological interplay within the microenvironment is required. In this study, we utilized wet lab migration experiments and quantitative histological data of human colorectal cancer tissue samples (n ¼ 20) including tumor cells, lymphocytes, stroma, and necrosis to generate a multiagent spatial model. The resulting data accurately reflected a wide range of situations of successful and failed immune surveillance. Validation of simulated tissue outcomes on an independent set of human colorectal cancer specimens (n ¼ 37) revealed the model recapitulated the spatial layout typically found in human tumors. Stroma slowed down tumor growth in a lymphocyte-deprived environment but promoted immune escape in a lymphocyteenriched environment. A subgroup of tumors with less stroma and high numbers of immune cells showed high rates of tumor control. These findings were validated using data from colorectal cancer patients (n ¼ 261). Low-density stroma and high lymphocyte levels showed increased overall survival (hazard ratio 0.322, P ¼ 0.0219) as compared with high stroma and high lymphocyte levels. To guide immunotherapy in colorectal cancer, simulation of immunotherapy in preestablished tumors showed that a complex landscape with optimal stroma permeabilization and immune cell activation is able to markedly increase therapy response in silico. These results can help guide the rational design of complex therapeutic interventions, which target the colorectal cancer microenvironment.

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Section: Histological Assessmentmentioning

confidence: 99%

Section: Histological Assessmentmentioning

confidence: 99%

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In Silico Modeling of Immunotherapy and Stroma-Targeting Therapies in Human Colorectal Cancer

et al. 2017

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“…The complete staining procedure was carried out on a BOND Max (Leica) and evaluated as previously described. 42,54 Tissue lysates were prepared from frozen material according to the manufacturer's instructions (Bio-Rad) and were used for cytokine detection, as previously described. 42,54 …”

Section: Immunohistochemistry and Cytokine Detectionmentioning

confidence: 99%

Identification of immunotherapeutic targets by genomic profiling of rectal NET metastases

et al. 2016

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Neuroendocrine tumors (NETs) of the gastrointestinal tract are a rare and heterogeneous group of neoplasms with unique tumor biology and clinical management issues. While surgery is the only curative treatment option in patients with early stage NETs, the optimal management strategy for patients with advanced metastatic NETs is unknown. Based on the tremendous success of immunotherapeutic approaches, we sought to investigate such approaches in a case of metastatic rectal NET. Here, we apply an integrative approach using various computational and experimental methods to explore several aspects of the tumor-host immune interactions for immunotherapeutic options. Sequencing of six different liver metastases revealed a quite homogenous set of mutations, and further analysis of these mutations for immunogenicity revealed few neo-epitopes with pre-existing T cell reactivity, which can be used in therapeutic vaccines. Staining for immunomodulatory proteins and cytokine profiling showed that the immune setting is surprisingly different, when compared to liver metastases of colorectal cancer for instance. Taken together, our results highlight the broad range and complexity of tumor-host immune interaction and underline the value of an integrative approach.

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“…The tumor stroma is rich in macrophages as the dominant type of immune cells, especially M2-polarized macrophages [2,17]. Several pathways that tumors use to create a T cell suppressive environment are activated.…”

Section: Specific Situation In Crcmentioning

confidence: 99%

Immunotherapy of Colorectal Cancer

Jäger

Halama²,

Zörnig³

et al. 2016

Oncol Res Treat

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It is known that the immune response, reflected by high T cell infiltrates in primary tumors and metastases, influences the clinical course of colorectal cancer (CRC). Therefore, immunotherapy concepts have been adapted from other tumor entities, which typically rely on the activation of T cells in the tumor microenvironment (e.g. blockade of the immune checkpoint molecules PD-1 and CTLA-4). However, most of the strategies using the approved checkpoint inhibitors and/or combination strategies have more or less failed to produce impressive results in early phase trials in CRC. Therefore, a number of novel targets for checkpoint inhibition are currently in early phase clinical testing (TIM-3, Lag-3, OX40, GITR, 4-1BB, CD40, CD70). A simple activation of infiltrating T cells will not, however, lead to a meaningful anti-tumor response without modulating the environmental factors in CRC. Thus, it is absolutely necessary to improve our understanding of the complex regulation of the tumor microenvironment in CRC to design individual combination treatments leading to effective immune control.

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Tumoral Immune Cell Exploitation in Colorectal Cancer Metastases Can Be Targeted Effectively by Anti-CCR5 Therapy in Cancer Patients

Cited by 419 publications

References 50 publications

In Silico Modeling of Immunotherapy and Stroma-Targeting Therapies in Human Colorectal Cancer

In Silico Modeling of Immunotherapy and Stroma-Targeting Therapies in Human Colorectal Cancer

Identification of immunotherapeutic targets by genomic profiling of rectal NET metastases

Immunotherapy of Colorectal Cancer

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