Predictive Biomarkers of Colon Cancer Immunotherapy: Present and Future

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2022 Dec 9

PMID 36483562

Authors

Wanting Hou

Cheng Yi

Hong Zhu

Affiliations

Soon will be listed here.

Abstract

Immunotherapy has revolutionized colon cancer treatment. Immune checkpoint inhibitors (ICIs) have shown clinical benefits for colon cancer patients, especially those with high microsatellite instability (MSI-H). In 2020, the US Food and Drug Administration (FDA)-approved ICI pembrolizumab as the first-line treatment for metastatic MSI-H colon cancer patients. Additionally, neoadjuvant immunotherapy has presented efficacy in treating early-stage colon cancer patients. Although MSI has been thought of as an effective predictive biomarker for colon cancer immunotherapy, only a small proportion of colon cancer patients were MSI-H, and certain colon cancer patients with MSI-H presented intrinsic or acquired resistance to immunotherapy. Thus, further search for predictive biomarkers to stratify patients is meaningful in colon cancer immunotherapy. Except for MSI, other biomarkers, such as PD-L1 expression level, tumor mutation burden (TMB), tumor-infiltrating lymphocytes (TILs), certain gut microbiota, ctDNA, and circulating immune cells were also proposed to be correlated with patient survival and ICI efficacy in some colon cancer clinical studies. Moreover, developing new diagnostic techniques helps identify accurate predictive biomarkers for colon cancer immunotherapy. In this review, we outline the reported predictive biomarkers in colon cancer immunotherapy and further discuss the prospects of technological changes for biomarker development in colon cancer immunotherapy.

Citing Articles

Unveiling the oncogenic role of SLC25A13: a multi-omics pan-cancer analysis reveals its impact on glioma progression.

Wu W, Liu S, Ren H, Rao Y, Nie J, Wei K Cancer Cell Int. 2025; 25(1):76.

PMID: 40033307 PMC: 11874833. DOI: 10.1186/s12935-025-03696-z.

Pan-cancer analysis identifies ADAM12 as a prognostic biomarker and indicator of immune infiltration in glioma.

Lv P, Zhang Y, Wu W, Jiang X, Xiang W Sci Rep. 2025; 15(1):6314.

PMID: 39984619 PMC: 11845722. DOI: 10.1038/s41598-025-90121-0.

Systemic immune profiling analysis identifying M2-TAM related genes predicted colon cancer prognosis and chemotherapy responses.

Liu X, Liu D, Tan C, Wang J Medicine (Baltimore). 2025; 103(52):e40979.

PMID: 39969348 PMC: 11688056. DOI: 10.1097/MD.0000000000040979.

Promising Cellular Immunotherapy for Colorectal Cancer Using Classical Dendritic Cells and Natural Killer T Cells.

Singer M, Valerin J, Zhang Z, Zhang Z, Dayyani F, Yaghmai V Cells. 2025; 14(3).

PMID: 39936958 PMC: 11817869. DOI: 10.3390/cells14030166.

Predicting patient outcomes with gene-expression biomarkers from colorectal cancer organoids and cell lines.

Razumovskaya A, Silkina M, Poloznikov A, Kulagin T, Raigorodskaya M, Gorban N Front Mol Biosci. 2025; 12:1531175.

PMID: 39886381 PMC: 11774744. DOI: 10.3389/fmolb.2025.1531175.

References

Khaliq A, Erdogan C, Kurt Z, Turgut S, Grunvald M, Rand T . Refining colorectal cancer classification and clinical stratification through a single-cell atlas. Genome Biol. 2022; 23(1):113. PMC: 9092724. DOI: 10.1186/s13059-022-02677-z. View

Cheng Y, Chen D, Chen P, He X, Li P, Lin Z . Association of Peripheral Blood Biomarkers With Response to Anti-PD-1 Immunotherapy for Patients With Deficient Mismatch Repair Metastatic Colorectal Cancer: A Multicenter Cohort Study. Front Immunol. 2022; 13:809971. PMC: 8850282. DOI: 10.3389/fimmu.2022.809971. View

Xu Y, Cao C, Zhu Z, Wang Y, Tan Y, Xu X . Novel Hypoxia-Associated Gene Signature Depicts Tumor Immune Microenvironment and Predicts Prognosis of Colon Cancer Patients. Front Genet. 2022; 13:901734. PMC: 9208084. DOI: 10.3389/fgene.2022.901734. View

Wang Y, Zhang L, Shi G, Liu M, Zhao W, Zhang Y . Effects of Inflammatory Response Genes on the Immune Microenvironment in Colorectal Cancer. Front Genet. 2022; 13:886949. PMC: 9032353. DOI: 10.3389/fgene.2022.886949. View

Simoni Y, Becht E, Fehlings M, Loh C, Koo S, Teng K . Bystander CD8 T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature. 2018; 557(7706):575-579. DOI: 10.1038/s41586-018-0130-2. View

Turksma A, Coupe V, Shamier M, Lam K, de Weger V, Belien J . Extent and Location of Tumor-Infiltrating Lymphocytes in Microsatellite-Stable Colon Cancer Predict Outcome to Adjuvant Active Specific Immunotherapy. Clin Cancer Res. 2015; 22(2):346-56. DOI: 10.1158/1078-0432.CCR-13-2462. View

Gao Y, Sun Z, Gu J, Li Z, Xu X, Xue C . Cancer-Associated Fibroblasts Promote the Upregulation of PD-L1 Expression Through Akt Phosphorylation in Colorectal Cancer. Front Oncol. 2021; 11:748465. PMC: 8640083. DOI: 10.3389/fonc.2021.748465. View

Wang C, Chevalier D, Saluja J, Sandhu J, Lau C, Fakih M . Regorafenib and Nivolumab or Pembrolizumab Combination and Circulating Tumor DNA Response Assessment in Refractory Microsatellite Stable Colorectal Cancer. Oncologist. 2020; 25(8):e1188-e1194. PMC: 7418365. DOI: 10.1634/theoncologist.2020-0161. View

Kuang C, Park Y, Augustin R, Lin Y, Hartman D, Seigh L . Pembrolizumab plus azacitidine in patients with chemotherapy refractory metastatic colorectal cancer: a single-arm phase 2 trial and correlative biomarker analysis. Clin Epigenetics. 2022; 14(1):3. PMC: 8740438. DOI: 10.1186/s13148-021-01226-y. View

10.

Baruch E, Youngster I, Ben-Betzalel G, Ortenberg R, Lahat A, Katz L . Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science. 2020; 371(6529):602-609. DOI: 10.1126/science.abb5920. View

11.

Luchini C, Bibeau F, Ligtenberg M, Singh N, Nottegar A, Bosse T . ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Ann Oncol. 2019; 30(8):1232-1243. DOI: 10.1093/annonc/mdz116. View

12.

de Vries N, van Unen V, Ijsselsteijn M, Abdelaal T, van der Breggen R, Sarasqueta A . High-dimensional cytometric analysis of colorectal cancer reveals novel mediators of antitumour immunity. Gut. 2019; 69(4):691-703. PMC: 7063399. DOI: 10.1136/gutjnl-2019-318672. View

13.

Clouthier D, Lien S, Yang S, Nguyen L, Manem V, Gray D . An interim report on the investigator-initiated phase 2 study of pembrolizumab immunological response evaluation (INSPIRE). J Immunother Cancer. 2019; 7(1):72. PMC: 6417194. DOI: 10.1186/s40425-019-0541-0. View

14.

Viale G, Trapani D, Curigliano G . Mismatch Repair Deficiency as a Predictive Biomarker for Immunotherapy Efficacy. Biomed Res Int. 2017; 2017:4719194. PMC: 5523547. DOI: 10.1155/2017/4719194. View

15.

Timmermann B, Kerick M, Roehr C, Fischer A, Isau M, Boerno S . Somatic mutation profiles of MSI and MSS colorectal cancer identified by whole exome next generation sequencing and bioinformatics analysis. PLoS One. 2011; 5(12):e15661. PMC: 3008745. DOI: 10.1371/journal.pone.0015661. View

16.

Kim J, Kim S, Baek J, Cha Y, Ahn J, Kim H . A Phase II Study of Avelumab Monotherapy in Patients with Mismatch Repair-Deficient/Microsatellite Instability-High or POLE-Mutated Metastatic or Unresectable Colorectal Cancer. Cancer Res Treat. 2020; 52(4):1135-1144. PMC: 7577804. DOI: 10.4143/crt.2020.218. View

17.

Wong S, Zhao L, Zhang X, Nakatsu G, Han J, Xu W . Gavage of Fecal Samples From Patients With Colorectal Cancer Promotes Intestinal Carcinogenesis in Germ-Free and Conventional Mice. Gastroenterology. 2017; 153(6):1621-1633.e6. DOI: 10.1053/j.gastro.2017.08.022. View

18.

Schrock A, Ouyang C, Sandhu J, Sokol E, Jin D, Ross J . Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer. Ann Oncol. 2019; 30(7):1096-1103. DOI: 10.1093/annonc/mdz134. View

19.

Guinney J, Dienstmann R, Wang X, De Reynies A, Schlicker A, Soneson C . The consensus molecular subtypes of colorectal cancer. Nat Med. 2015; 21(11):1350-6. PMC: 4636487. DOI: 10.1038/nm.3967. View

20.

Sargent D, Marsoni S, Monges G, Thibodeau S, Labianca R, Hamilton S . Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol. 2010; 28(20):3219-26. PMC: 2903323. DOI: 10.1200/JCO.2009.27.1825. View