IFNγ signaling integrity in colorectal cancer immunity and immunotherapy

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Abstract

The majority of colorectal cancer patients are not responsive to immune checkpoint blockade (ICB). The interferon gamma (IFNγ) signaling pathway drives spontaneous and ICB-induced antitumor immunity. In this review, we summarize recent advances in the epigenetic, genetic, and functional integrity of the IFNγ signaling pathway in the colorectal cancer microenvironment and its immunological relevance in the therapeutic efficacy of and resistance to ICB. Moreover, we discuss how to target IFNγ signaling to inform novel clinical trials to treat patients with colorectal cancer.

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PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.

Dung Le, Jennifer Uram, Hao Wang … (2015)

Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade.

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Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

Dung Le, Jennifer N. Durham, Kellie N Smith … (2017)

The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers' tissue of origin.

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Colorectal cancer statistics, 2020

Rebecca Siegel, Kimberly D Miller, Ann Goding Sauer … (2020)

Colorectal cancer (CRC) is the second most common cause of cancer death in the United States. Every 3 years, the American Cancer Society provides an update of CRC occurrence based on incidence data (available through 2016) from population-based cancer registries and mortality data (through 2017) from the National Center for Health Statistics. In 2020, approximately 147,950 individuals will be diagnosed with CRC and 53,200 will die from the disease, including 17,930 cases and 3,640 deaths in individuals aged younger than 50 years. The incidence rate during 2012 through 2016 ranged from 30 (per 100,000 persons) in Asian/Pacific Islanders to 45.7 in blacks and 89 in Alaska Natives. Rapid declines in incidence among screening-aged individuals during the 2000s continued during 2011 through 2016 in those aged 65 years and older (by 3.3% annually) but reversed in those aged 50 to 64 years, among whom rates increased by 1% annually. Among individuals aged younger than 50 years, the incidence rate increased by approximately 2% annually for tumors in the proximal and distal colon, as well as the rectum, driven by trends in non-Hispanic whites. CRC death rates during 2008 through 2017 declined by 3% annually in individuals aged 65 years and older and by 0.6% annually in individuals aged 50 to 64 years while increasing by 1.3% annually in those aged younger than 50 years. Mortality declines among individuals aged 50 years and older were steepest among blacks, who also had the only decreasing trend among those aged younger than 50 years, and excluded American Indians/Alaska Natives, among whom rates remained stable. Progress against CRC can be accelerated by increasing access to guideline-recommended screening and high-quality treatment, particularly among Alaska Natives, and elucidating causes for rising incidence in young and middle-aged adults.

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Author and article information

Contributors

Weiping Zou:

ORCID: http://orcid.org/0000-0001-7952-3549

wzou@med.umich.edu

Journal

Journal ID (nlm-ta): Cell Mol Immunol

Journal ID (iso-abbrev): Cell Mol Immunol

Title: Cellular and Molecular Immunology

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 1672-7681

ISSN (Electronic): 2042-0226

Publication date (Electronic): 12 August 2021

Publication date PMC-release: 12 August 2021

Publication date (Print): January 2022

Volume: 19

Issue: 1

Pages: 23-32

Affiliations

[1 ]GRID grid.214458.e, ISNI 0000000086837370, Department of Surgery, , University of Michigan School of Medicine, ; Ann Arbor, MI USA

[2 ]GRID grid.214458.e, ISNI 0000000086837370, Center of Excellence for Cancer Immunology and Immunotherapy, Rogel Cancer Center, , University of Michigan School of Medicine, ; Ann Arbor, MI USA

[3 ]GRID grid.214458.e, ISNI 0000000086837370, Department of Radiation Oncology, , University of Michigan School of Medicine, ; Ann Arbor, MI USA

[4 ]GRID grid.214458.e, ISNI 0000000086837370, Veterans Affairs Ann Arbor Healthcare System, , University of Michigan School of Medicine, ; Ann Arbor, MI USA

[5 ]GRID grid.214458.e, ISNI 0000000086837370, Graduate Programs in Immunology, , University of Michigan School of Medicine, ; Ann Arbor, MI USA

[6 ]GRID grid.214458.e, ISNI 0000000086837370, Tumor Biology, , University of Michigan School of Medicine, ; Ann Arbor, MI USA

[7 ]GRID grid.214458.e, ISNI 0000000086837370, Department of Pathology, , University of Michigan School of Medicine, ; Ann Arbor, MI USA

Author information

Weiping Zou http://orcid.org/0000-0001-7952-3549

Article

Publisher ID: 735

DOI: 10.1038/s41423-021-00735-3

PMC ID: 8752802

PubMed ID: 34385592

SO-VID: 31f1946f-dec4-4178-95cc-236b64e373af

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 6 May 2021

Date accepted : 21 June 2021

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ScienceOpen disciplines: Immunology

Keywords: ifngr,interferon,mhc,palmitoylation,t cell,ezh2,arid1a,pd-1,pd-l1,apoptosis,ferroptosis,colorectal cancer, immunity,oncology,immunosuppression

Data availability:

ScienceOpen disciplines: Immunology

Keywords: ifngr, interferon, mhc, palmitoylation, t cell, ezh2, arid1a, pd-1, pd-l1, apoptosis, ferroptosis, colorectal cancer, immunity, oncology, immunosuppression

IFNγ signaling integrity in colorectal cancer immunity and immunotherapy

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Most cited references 128

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.

Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

Colorectal cancer statistics, 2020

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