Histidine and Immunotherapy Response in Colorectal Cancer

Mechanistic Study of Histidine-mediated Regulation of Antigen Presentation in Colorectal Cancer to Enhance Sensitivity to Immunotherapy

This observational study aims to investigate the role of histidine and its transporter SLC15A3 in modulating the sensitivity of colorectal cancer to immunotherapy. By analyzing the expression of SLC15A3 in tumor/normal colonic tissues from patients with colorectal cancer and assessing serum histidine metabolic levels, the study seeks to identify potential targets associated with therapeutic resistance and explore possible intervention strategies to improve immune checkpoint blockade treatment efficacy.

Study Overview

• Status: Not yet recruiting
• Conditions: Colorectal Cancer
• Intervention / Treatment: Other: Immunohistochemistry or immunofluorescence; Other: Flow cytometry; Other: Serum metabolomic analysis or ELISA

• Study Type: Observational
• Enrollment (Estimated): 150

Contacts and Locations

• Study Contact: Name: Wan Du, M.D.; Phone Number: (86)13788972966; Email: duwan2017@126.com
• Study Contact Backup: Name: Youli Chen; Phone Number: (86)13656503169; Email: chenylpetri@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients with pathologically confirmed colorectal cancer who received care at the Department of Gastroenterology, Department of Oncology, or Department of General Surgery at Renji Hospital, Shanghai Jiao Tong University School of Medicine.

Description

Inclusion Criteria:

1. Participants aged ≥18 years and ≤100 years.
2. Patients pathologically diagnosed with colorectal cancer based on colonoscopy or surgical specimens and biopsy examination; or patients who previously received PD-1 monoclonal antibody immunotherapy for colorectal cancer.

Exclusion Criteria:

1. Age <18 years.
2. Presence of poorly controlled metabolic diseases, including hypertension, diabetes mellitus, hyperlipidemia, hyperuricemia, or hyperthyroidism.
3. Presence of other severe gastrointestinal diseases, including inflammatory bowel disease, ischemic bowel disease, familial adenomatous polyposis, liver cirrhosis, MUTYH-associated polyposis (MAP), Lynch syndrome (LS), or Peutz-Jeghers syndrome (PJS).
4. History of other malignant tumors, or pathological diagnosis of colorectal inflammatory polyps, hyperplastic polyps, neuroendocrine tumors, neuroendocrine carcinoma, or mixed neuroendocrine-non-neuroendocrine neoplasms.
5. History of neurological or psychiatric disorders, such as epilepsy or depression.
6. Unqualified specimens, including hemolyzed serum samples or tissue samples that were not properly preserved in time.

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Colorectal cancer patients; Patients with pathologically confirmed colorectal cancer. Colorectal tumor and adjacent normal tissue specimens will be analyzed for SLC15A3 expression, or serum specimen will be analyzed for histidine-related metabolites, or whole blood samples will be analyzed for peripheral blood immune cell functions.	Other: Immunohistochemistry or immunofluorescence; Formalin-fixed paraffin-embedded (FFPE) colorectal tumor and adjacent normal tissue specimens will be analyzed for SLC15A3 expression by immunohistochemistry and/or immunofluorescence.; Other: Flow cytometry; Peripheral blood mononuclear cells (PBMCs) will be separated from whole blood samples and assessed for immune cell phenotype and functional markers by flow cytometry.
ICB responders; Patients with colorectal cancer who previously received PD-1 immune checkpoint blockade and achieved a clinical response. Tumor tissue will be analyzed for SLC15A3 expression, and serum specimen will be analyzed for histidine-related metabolites.	Other: Immunohistochemistry or immunofluorescence; Formalin-fixed paraffin-embedded (FFPE) colorectal tumor and adjacent normal tissue specimens will be analyzed for SLC15A3 expression by immunohistochemistry and/or immunofluorescence.; Other: Serum metabolomic analysis or ELISA; Serum specimens from patients with colorectal cancer will be analyzed for histidine and related metabolites and selected biomarkers by metabolomics and/or ELISA.
ICB non-responders; Patients with colorectal cancer who previously received PD-1 immune checkpoint blockade and did not achieve a clinical response. Tumor tissue will be analyzed for SLC15A3 expression, and serum specimen will be analyzed for histidine-related metabolites.	Other: Immunohistochemistry or immunofluorescence; Formalin-fixed paraffin-embedded (FFPE) colorectal tumor and adjacent normal tissue specimens will be analyzed for SLC15A3 expression by immunohistochemistry and/or immunofluorescence.; Other: Serum metabolomic analysis or ELISA; Serum specimens from patients with colorectal cancer will be analyzed for histidine and related metabolites and selected biomarkers by metabolomics and/or ELISA.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SLC15A3 expression	SLC15A3 expression measured by immunohistochemistry (IHC) or immunofluorescence in formalin-fixed paraffin-embedded colorectal tumor and adjacent normal tissue specimens.	Baseline archival tissue specimen from surgical resection or diagnostic biopsy.
Serum histidine concentration	Serum histidine concentration measured using liquid chromatography-mass spectrometry (LC-MS) in serum samples collected before treatment initiation and, where available, after 9 weeks (one round of treatment).	Baseline and after 9 weeks (one round of treatment).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival	Progression-free survival, defined as the time from initial diagnosis or treatment initiation to documented disease progression, recurrence, or death from any cause, whichever occurs first, in patients with colorectal cancer with available follow-up information.	5 years.
Overall survival	Overall survival, defined as the time from initial diagnosis or treatment initiation to death from any cause in patients with colorectal cancer with available follow-up information.	5 years.
Percentage of IFN-gamma-positive T cells	Peripheral blood mononuclear cells (PBMCs) from archived blood samples of patients with colorectal cancer will be assessed by flow cytometry to evaluate the percentage of IFN-gamma-positive T cells as a T cell effector function marker. Samples collected before treatment initiation and, where available, after 9 weeks (one round of treatment) will be analyzed.	Baseline and after 9 weeks (one round of treatment).
Percentage of granzyme B-positive T cells	Peripheral blood mononuclear cells (PBMCs) from archived blood samples of patients with colorectal cancer will be assessed by flow cytometry to evaluate the percentage of granzyme B-positive T cells as a T cell effector function marker. Samples collected before treatment initiation and, where available, after 9 weeks (one round of treatment) will be analyzed.	Baseline and after 9 weeks (one round of treatment).
Clinicopathological characteristics	Clinicopathological characteristics of patients with colorectal cancer, including age, sex, tumor location, AJCC TNM stage, and histological grade, extracted from available medical records.	Baseline at initial diagnosis or tissue collection.

Collaborators and Investigators

• Sponsor: Jing-yuan Fang, MD, Ph. D
• Investigators: Principal Investigator: Jing-Yuan Fang, M.D., Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, Renji Hospital, School of Medicine, Shanghai Jiao Tong University

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: April 24, 2026
• First Submitted That Met QC Criteria: May 12, 2026
• First Posted (Actual): May 14, 2026

Study Record Updates

• Last Update Posted (Actual): May 14, 2026
• Last Update Submitted That Met QC Criteria: May 12, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Colorectal cancer; immune checkpoint blockade; Histidine
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Cytological Techniques; Chemistry Techniques, Analytical; Cell Separation; Histocytochemistry; Histological Techniques; Immunologic Techniques; Photometry; Fluorometry; Luminescent Measurements; Cytophotometry; Molecular Probe Techniques; Immunoenzyme Techniques; Immunoassay; Immunosorbent Techniques; Immunohistochemistry; Flow Cytometry; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique
• Other Study ID Numbers: KY2025-053-B

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No