Patient stratification based on urea cycle metabolism for exploration of combination immunotherapy in colon cancer.

Publisher: BioMed Central Country of Publication: England NLM ID: 100967800 Publication Model: Electronic Cited Medium: Internet ISSN: 1471-2407 (Electronic) Linking ISSN: 14712407 NLM ISO Abbreviation: BMC Cancer Subsets: MEDLINE

Original Publication: London : BioMed Central, [2001-

Colonic Neoplasms*/drug therapy ; Colonic Neoplasms*/genetics ; Immunotherapy*/methods; Cohort Studies ; Humans ; Immunologic Factors ; Urea

Background: Owing to the low ratio of patients benefitting from immunotherapy, patient stratification becomes necessary. An accurate patient stratification contributes to therapy for different tumor types. Therefore, this study aimed to subdivide colon cancer patients for improved combination immunotherapy.
Methods: We characterized the patients based on urea cycle metabolism, performed a consensus clustering analysis and constructed a risk model in the cancer genome atlas cohort. Colon cancer patients were further categorized into two tags: clusters, and risk groups, for the exploration of combination immunotherapy. In addition to external validation in the Gene Expression Omnibus datasets, several images of immunohistochemistry were used for further validation.
Results: Patient characterization based on urea cycle metabolism was related to immune infiltration. An analysis of consensus clustering and immune infiltration generated a cluster distribution and identified patients in cluster 1 with high immune infiltration levels as hot tumors for immunotherapy. A risk model of seven genes was constructed to subdivide the patients into low- and high-risk groups. Validation was performed using a cohort of 731 colon cancer patients. Patients in cluster 1 had a higher immunophenoscore (IPS) in immune checkpoint inhibitor therapy, and those other risk groups displayed varying sensitivities to potential combination immunotherapeutic agents. Finally, we subdivided the colon cancer patients into four groups to explore combination immunotherapy. Immunohistochemistry analysis showed that protein expression of two genes were upregulated while that of other two genes were downregulated or undetected in cancerous colon tissues.
Conclusion: Using subdivision to combine chemotherapy with immunotherapy would not only change the dilemma of immunotherapy in not hot tumors, but also promote the proposition of more rational personalized therapy strategies in future.
(© 2022. The Author(s).)

Cancers (Basel). 2021 Jul 14;13(14):. (PMID: 34298744)
Front Immunol. 2018 Sep 25;9:2159. (PMID: 30319622)
Nat Commun. 2019 Jul 5;10(1):3000. (PMID: 31278254)
J Cell Mol Med. 2021 Apr;25(8):3870-3884. (PMID: 33611848)
J Hematol Oncol. 2020 Aug 10;13(1):110. (PMID: 32778143)
Nat Rev Gastroenterol Hepatol. 2019 Jun;16(6):361-375. (PMID: 30886395)
Nat Rev Gastroenterol Hepatol. 2016 Dec;13(12):691-706. (PMID: 27848961)
Front Immunol. 2021 Oct 26;12:734745. (PMID: 34764953)
Mol Cell. 2021 Sep 16;81(18):3749-3759. (PMID: 34469752)
Gastroenterology. 2020 Jan;158(2):341-353. (PMID: 31394082)
Cell Metab. 2016 Jan 12;23(1):27-47. (PMID: 26771115)
PLoS Med. 2013;10(5):e1001453. (PMID: 23700391)
Database (Oxford). 2010 Aug 05;2010:baq020. (PMID: 20689021)
Sci Adv. 2019 Feb 20;5(2):eaav2437. (PMID: 30801016)
Cancer Res. 2017 Nov 1;77(21):e108-e110. (PMID: 29092952)
Bioinformatics. 2010 Jun 15;26(12):1572-3. (PMID: 20427518)
Nat Commun. 2019 Feb 6;10(1):620. (PMID: 30728358)
BMC Bioinformatics. 2013 Aug 10;14:244. (PMID: 23937229)
Database (Oxford). 2016 Apr 05;2016:. (PMID: 27048349)
Front Immunol. 2018 Jul 30;9:1774. (PMID: 30105035)
Brief Bioinform. 2021 Nov 5;22(6):. (PMID: 34237133)
Front Immunol. 2020 Aug 12;11:2039. (PMID: 32903444)
Nat Biotechnol. 2020 Jun;38(6):675-678. (PMID: 32444850)
Cancer Lett. 2019 Sep 10;459:248-267. (PMID: 31132429)
Lancet. 2018 Mar 17;391(10125):1023-1075. (PMID: 29395269)
Cell Mol Biol Lett. 2019 Jun 13;24:40. (PMID: 31223315)
Clin Cancer Res. 2013 Jan 15;19(2):393-403. (PMID: 23204132)
J Immunother Cancer. 2020 Oct;8(2):. (PMID: 33028695)
Cell Rep. 2017 Jan 3;18(1):248-262. (PMID: 28052254)
Nat Rev Drug Discov. 2019 Mar;18(3):197-218. (PMID: 30610226)
Comput Struct Biotechnol J. 2021 May 26;19:3470-3481. (PMID: 34188784)
Nat Rev Cancer. 2018 Oct;18(10):634-645. (PMID: 30194362)
Genome Med. 2022 Feb 24;14(1):20. (PMID: 35197093)
Hum Pathol. 2017 Oct;68:193-202. (PMID: 28882699)
Genome Res. 2012 Mar;22(3):568-76. (PMID: 22300766)
CA Cancer J Clin. 2018 Nov;68(6):394-424. (PMID: 30207593)
Int J Cancer. 2019 Oct 15;145(8):2201-2208. (PMID: 30485425)
Gastroenterology. 2010 Mar;138(3):958-68. (PMID: 19914252)

81871915 National Natural Science Foundation of China; 2022A1515012140 Natural Science Foundation of Guangdong Province; 201607010050 Guangzhou Municipal Science and Technology Project

Keywords: Colon cancer; Combination immunotherapy; Hot tumors; Subdividing; Urea cycle metabolism

0 (Immunologic Factors)
8W8T17847W (Urea)

Date Created: 20220812 Date Completed: 20220816 Latest Revision: 20220816

20240829

PMC9375340

10.1186/s12885-022-09958-7

35962309