Immunogenomic Classification of Colorectal Cancer and Therapeutic Implications

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Abstract

The immune system has a substantial effect on colorectal cancer (CRC) progression. Additionally, the response to immunotherapeutics and conventional treatment options (e.g., chemotherapy, radiotherapy and targeted therapies) is influenced by the immune system. The molecular characterization of colorectal cancer (CRC) has led to the identification of favorable and unfavorable immunological attributes linked to clinical outcome. With the definition of consensus molecular subtypes (CMSs) based on transcriptomic profiles, multiple characteristics have been proposed to be responsible for the development of the tumor immune microenvironment and corresponding mechanisms of immune escape. In this review, a detailed description of proposed immune phenotypes as well as their interaction with different therapeutic modalities will be provided. Finally, possible strategies to shift the CRC immune phenotype towards a reactive, anti-tumor orientation are proposed per CMS.

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Most cited references 79

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HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C.

V Braud, D. Allan, C A O'Callaghan … (1998)

The protein HLA-E is a non-classical major histocompatibility complex (MHC) molecule of limited sequence variability. Its expression on the cell surface is regulated by the binding of peptides derived from the signal sequence of some other MHC class I molecules. Here we report the identification of ligands for HLA-E. We constructed tetramers in which recombinant HLA-E and beta2-microglobulin were refolded with an MHC leader-sequence peptide, biotinylated, and conjugated to phycoerythrin-labelled Extravidin. This HLA-E tetramer bound to natural killer (NK) cells and a small subset of T cells from peripheral blood. On transfectants, the tetramer bound to the CD94/NKG2A, CD94/NKGK2B and CD94/NKG2C NK cell receptors, but did not bind to the immunoglobulin family of NK cell receptors (KIR). Surface expression of HLA-E was enough to protect target cells from lysis by CD94/NKG2A+ NK-cell clones. A subset of HLA class I alleles has been shown to inhibit killing by CD94/NKG2A+ NK-cell clones. Only the HLA alleles that possess a leader peptide capable of upregulating HLA-E surface expression confer resistance to NK-cell-mediated lysis, implying that their action is mediated by HLA-E, the predominant ligand for the NK cell inhibitory receptor CD94/NKG2A.

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Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer.

Christine Ribic, Daniel Sargent, Malcolm J Moore … (2003)

Colon cancers with high-frequency microsatellite instability have clinical and pathological features that distinguish them from microsatellite-stable tumors. We investigated the usefulness of microsatellite-instability status as a predictor of the benefit of adjuvant chemotherapy with fluorouracil in stage II and stage III colon cancer. Tumor specimens were collected from patients with colon cancer who were enrolled in randomized trials of fluorouracil-based adjuvant chemotherapy. Microsatellite instability was assessed with the use of mononucleotide and dinucleotide markers. Of 570 tissue specimens, 95 (16.7 percent) exhibited high-frequency microsatellite instability. Among 287 patients who did not receive adjuvant therapy, those with tumors displaying high-frequency microsatellite instability had a better five-year rate of overall survival than patients with tumors exhibiting microsatellite stability or low-frequency instability (hazard ratio for death, 0.31 [95 percent confidence interval, 0.14 to 0.72]; P=0.004). Among patients who received adjuvant chemotherapy, high-frequency microsatellite instability was not correlated with increased overall survival (hazard ratio for death, 1.07 [95 percent confidence interval, 0.62 to 1.86]; P=0.80). The benefit of treatment differed significantly according to the microsatellite-instability status (P=0.01). Adjuvant chemotherapy improved overall survival among patients with microsatellite-stable tumors or tumors exhibiting low-frequency microsatellite instability, according to a multivariate analysis adjusted for stage and grade (hazard ratio for death, 0.72 [95 percent confidence interval, 0.53 to 0.99]; P=0.04). By contrast, there was no benefit of adjuvant chemotherapy in the group with high-frequency microsatellite instability. Fluorouracil-based adjuvant chemotherapy benefited patients with stage II or stage III colon cancer with microsatellite-stable tumors or tumors exhibiting low-frequency microsatellite instability but not those with tumors exhibiting high-frequency microsatellite instability. Copyright 2003 Massachusetts Medical Society

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Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment.

Helena Harlin, Yuru Meng, Amy C Peterson … (2009)

Despite the frequent detection of circulating tumor antigen-specific T cells, either spontaneously or following active immunization or adoptive transfer, immune-mediated cancer regression occurs only in the minority of patients. One theoretical rate-limiting step is whether effector T cells successfully migrate into metastatic tumor sites. Affymetrix gene expression profiling done on a series of metastatic melanoma biopsies revealed a major segregation of samples based on the presence or absence of T-cell-associated transcripts. The presence of lymphocytes correlated with the expression of defined chemokine genes. A subset of six chemokines (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10) was confirmed by protein array and/or quantitative reverse transcription-PCR to be preferentially expressed in tumors that contained T cells. Corresponding chemokine receptors were found to be up-regulated on human CD8(+) effector T cells, and transwell migration assays confirmed the ability of each of these chemokines to promote migration of CD8(+) effector cells in vitro. Screening by chemokine protein array identified a subset of melanoma cell lines that produced a similar broad array of chemokines. These melanoma cells more effectively recruited human CD8(+) effector T cells when implanted as xenografts in nonobese diabetic/severe combined immunodeficient mice in vivo. Chemokine blockade with specific antibodies inhibited migration of CD8(+) T cells. Our results suggest that lack of critical chemokines in a subset of melanoma metastases may limit the migration of activated T cells, which in turn could limit the effectiveness of antitumor immunity.

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Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 24 October 2017

Publication date Collection: October 2017

Volume: 18

Issue: 10

Electronic Location Identifier: 2229

Affiliations

[1 ]Tumor Biology, Immunology, and Therapy Section, Immunology, Inflammation, and Metabolism Department, Division of Translational Medicine, Sidra Medical and Research Center, PO Box 26999 Doha, Qatar; jroelands@ 123456sidra.org (J.R.); cmaccalli@ 123456sidra.org (C.M.)

[2 ]Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; P.J.K.Kuppen@ 123456lumc.nl

[3 ]Academic Medical Center Amsterdam, Center for Experimental Molecular Medicine, 1105AZ Amsterdam, The Netherlands; l.vermeulen@ 123456amc.uva.nl

[4 ]Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, PO Box 5825 Doha, Qatar; jdecock@ 123456hbku.edu.qa

[5 ]Office of the Chief Research Officer (CRO), Sidra Medical and Research Center, PO Box 26999 Doha, Qatar; ewang@ 123456sidra.org (E.W.); francesco.marincola@ 123456abbvie.com (F.M.M.)

Author notes

[* ]Correspondence: dbedognetti@ 123456sidra.org (D.B.); whendrickx@ 123456sidra.org (W.H.); Tel.: +974-4003-7408 (D.B.); +974-4003-7409 (W.H.)

[†]

Current employer: Abbvie Biotherapeutics Corporation, 94063 Redwood City, CA, USA.

[‡]

These authors contributed equally to this work.

Author information

Jessica Roelands https://orcid.org/0000-0003-3631-2041

Peter J. K. Kuppen https://orcid.org/0000-0002-0294-3251

Julie Decock https://orcid.org/0000-0002-4409-100X

Wouter Hendrickx https://orcid.org/0000-0002-7649-5092

Article

Publisher ID: ijms-18-02229

DOI: 10.3390/ijms18102229

PMC ID: 5666908

PubMed ID: 29064420

SO-VID: 56be006e-687f-4c8a-ba0d-4106a4e5ef4a

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Immunogenomic Classification of Colorectal Cancer and Therapeutic Implications

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Karger: Oncology

Most cited references 79

HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C.

Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer.

Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment.

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