The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints
Open accessPublished version of a preprint
Abstract
We examined the immune microenvironment of primary colorectal cancer using immunohistochemistry, laser capture microdissection/qRT-PCR, flow cytometry, and functional analysis of tumor-infiltrating lymphocytes. A subset of colorectal cancer displayed high infiltration with activated CD8+ cytotoxic T lymphocyte (CTL) as well as activated Th1 cells characterized by IFNγ production and the Th1 transcription factor TBET. Parallel analysis of tumor genotypes revealed that virtually all of the tumors with this active Th1/CTL microenvironment had defects in mismatch repair, as evidenced by microsatellite instability (MSI). Counterbalancing this active Th1/CTL microenvironment, MSI tumors selectively demonstrated highly upregulated expression of multiple immune checkpoints, including five—PD-1, PD-L1, CTLA-4, LAG-3, and IDO—currently being targeted clinically with inhibitors. These findings link tumor genotype with the immune microenvironment, and explain why MSI tumors are not naturally eliminated despite a hostile Th1/CTL microenvironment. They further suggest that blockade of specific checkpoints may be selectively efficacious in the MSI subset of colorectal cancer. Significance: The findings reported in this article are the first to demonstrate a link between a genetically defined subtype of cancer and its corresponding expression of immune checkpoints in the tumor microenvironment. The mismatch repair–defective subset of colorectal cancer selectively upregulates at least five checkpoint molecules that are targets of inhibitors currently being clinically tested. Cancer Discov; 5(1); 43–51. ©2014 AACR. See related commentary by Xiao and Freeman, p. 16 This article is highlighted in the In This Issue feature, p. 1
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
MSI-H results in upregulation of immune checkpoint proteins such as PD-1 and PD-L1, facilitating immune evasion via tumor-infiltrating lymphocytes rather than tumor cells.
“Moreover, MSI-H results in the upregulation of immune checkpoint proteins (like PD-1 and PD-L1), facilitating immune evasion via tumor-infiltrating lymphocytes, rather than tumor cells [71].”
From Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy (2024) · cites this paper as [71]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 28 · Cited by 1,487
- Authors
- Llosa, N. J., Cruise, M., Tam, A., Wicks, E. C., Hechenbleikner, E. M., Taube, J. M., Blosser, R. L., Fan, H., Wang, H., Luber, B. S., Zhang, M., Papadopoulos, N., Kinzler, K. W., Vogelstein, B., Sears, C. L., Anders, R. A., Pardoll, D. M., & Housseau, F.
- Affiliations
- Johns Hopkins University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Pardoll, Drew M.
- Housseau, Franck
- ORCID
- Venue
- Cancer Discovery
- Published
- 2015-01-01
- Volume
- 5
- Issue
- 1
- Pages
- 43-51
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC4293246
- OpenAlex
- W1984642649
- Cited by
- 1,487
- References
- 28
- Citations by year
- 2026: 89 · 2025: 105 · 2024: 102 · 2023: 139 · 2022: 142 · 2021: 168 · 2020: 140 · 2019: 150 · 2018: 142 · 2017: 129 · 2016: 125 · 2015: 55 · 2014: 1
- FWCI
- 49.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- National Cancer Institute (T32CA126607, R01CA151393, P50CA062924, P30CA006973)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK089502, K08DK087856)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- microsatellite instability, colorectal cancer, tumor immune microenvironment, immune checkpoint, PD-1, PD-L1, CTLA-4, LAG-3, IDO, mismatch repair deficiency, CD8+ cytotoxic T lymphocytes, Th1 cells, interferon-gamma, tumor-infiltrating lymphocytes, cancer immunotherapy
- MeSH terms
- Colonic Neoplasms, Humans, Immunohistochemistry, Phenotype, Immunophenotyping, T-Lymphocyte Subsets, Lymphocytes, Tumor-Infiltrating, Stromal Cells, Microsatellite Instability, Tumor Microenvironment, Cell Cycle Checkpoints
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
