The Status of Immune Checkpoints at Gastrointestinal Cancer

Determination of Immune Check Point Levels in Paracentesis Samples of Gastrointestinal System Malignancy Cases

Colorectal cancers are the third most common cancer in the world. In advanced stages of colorectal cancers, peritoneal carcinomatosis and intraabdominal acid development occur. Although stomach cancer is the 5th most common cancer in the world, it is the third cancer with the highest mortality. Pancreatic cancer is one of the highest mortality cancers worldwide. Likewise, in advanced stages of stomach and pancreatic cancer, peritoneal carcinomatosis and intra- abdominal acid development occur. It is known that the immune system plays an important role in tumor development or destruction of tumor. Recent studies have shown that tumor cells develop escape mechanisms in the tumor microenvironment to escape from host immunity. It has been reported that differentiation of T cells towards Th2 and regulatory T cells is also effective in tumor progression(6). Changes in the tumor microenvironment and immune checkpoints are important mechanisms that lead to escape from the immune system. Immune checkpoints are on the agenda especially after 2018 Nobel Prize and they are important molecules in revealing the relationship.In our study, it is aimed to evaluate whether there is a difference in immune control points in patients with end-stage colorectal cancer, gastric cancer and pancreatic cancer compared to patients without malignancy, and the relationship of these parameters with patient survival and tumor spread mechanisms.

Study Overview

• Status: Completed
• Conditions: Gastrointestinal Cancer
• Intervention / Treatment: Diagnostic test: Flow cytometric analysis

Detailed Description

Colorectal cancers are the third most common cancer in the world. In advanced stages of colorectal cancers, peritoneal carcinomatosis and intraabdominal acid development occur. Although stomach cancer is the 5th most common cancer in the world, it is the third cancer with the highest mortality. Pancreatic cancer is one of the highest mortality cancers worldwide. Likewise, in advanced stages of stomach and pancreatic cancer, peritoneal carcinomatosis and intra- abdominal acid development occur. It is known that the immune system plays an important role in tumor development or destruction of tumor. Recent studies have shown that tumor cells develop escape mechanisms in the tumor microenvironment to escape from host immunity. It has been reported that differentiation of T cells towards Th2 and regulatory T cells is also effective in tumor progression(6). Changes in the tumor microenvironment and immune checkpoints are important mechanisms that lead to escape from the immune system. Immune checkpoints are on the agenda especially after 2018 Nobel Prize and they are important molecules in revealing the relationship.

Programmed Cell Death Protein-1 (PD-1) and its ligand, PD-L1, is an immune control point that acts by blocking T cell receptor signal transduction and co-stimuli. T cell immunoglobulin and mucin domain 3 (TIM-3) are mostly expressed on interferon-gamma-producing T cells, Tregs, dendritic cells, B cells, macrophages, natural killer cells (NK) and mast cells. Enhanced regulation of TIM-3 expression is associated with autoimmune diseases. High TIM-3 expression is associated with suppression of T cell responses and T cell depletion characterized by loss of T cell functions during chronic viral infections and during tumor development. With the clinical success of immune checkpoint inhibitors such as ipilimumab and nivolumab for melanoma and lung cancer, immune checkpoints have received more attention.

The role of the immune system in colorectal cancers has been demonstrated, especially in recent studies, with the effects of tumor-infiltrating lymphocytes (TIL) and immune control points on TILs or immune control point ligands on patient survival. Studies in the literature usually include immunological examinations of patient blood or tumor tissue.

There are many publications in the literature on the study of immunological markers from acid fluid samples for various reasons. In these studies, T and B cell subtypes were examined from acid fluids samples taken from patients with spontaneous ascites, especially ovarian cancer and liver cirrhosis. In the only study conducted on gastrointestinal cancers, immunophenotyping was performed in intraabdominal ascites and blood in 22 advanced gastrointestinal tumor patients, and some cell subgroups were associated with clinical worsening.

In the literature, there is no study on immune control points from intra-abdominal acid fluids specific to gastric and colorectal cancer. In our study, it is aimed to evaluate whether there is a difference in immune control points in patients with end-stage colorectal cancer, gastric cancer and pancreatic cancer compared to patients without malignancy, and the relationship of these parameters with patient survival and tumor spread mechanisms.

• Study Type: Observational
• Enrollment (Actual): 50

Contacts and Locations

Study Locations

• Turkey
  • Istanbul, Turkey, 34098
    • Istanbul Training and Reseach Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with intraabdominal ascites with benign reasons (liver cirrhosis, Congestive heart failure, etc.) will be the control group, and patients with advanced stage colorectal cancer, gastric cancer and pancreatic cancer who develop malignant ascites will be the gastrointestinal cancer group

Description

Inclusion Criteria:

• Patients with intraabdominal ascites with benign reasons (liver cirrhosis, Congestive heart failure, etc.) for control group
• Patients with advanced stage colorectal cancer, gastric cancer and pancreatic cancer who develop malignant ascites for gastrointestinal cancer group

Exclusion Criteria:

• Pregnant
• Primary immune system failure
• HIV patients

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Gastrointestinal cancers; Patients with advanced stage colorectal cancer, gastric cancer and pancreatic cancer who develop malignant ascites	Diagnostic test: Flow cytometric analysis; Measuring the sCD25 (IL-2Ra), 4-1BB, B7.2 (CD86), Free Active TGF-β1, CTLA-4, PD-L1, PD-1, Tim-3, LAG-3, Galectin-9 levels with flow cytometry
Control; Patients with intraabdominal ascites with benign reasons (liver cirrhosis, Congestive heart failure, etc.) .	Diagnostic test: Flow cytometric analysis; Measuring the sCD25 (IL-2Ra), 4-1BB, B7.2 (CD86), Free Active TGF-β1, CTLA-4, PD-L1, PD-1, Tim-3, LAG-3, Galectin-9 levels with flow cytometry

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immune Checkpoints	sCD25 (IL-2Ra), 4-1BB, B7.2 (CD86), Free Active TGF-β1, CTLA-4, PD-L1, PD-1, Tim-3, LAG-3, Galectin-9	4 months

Collaborators and Investigators

• Sponsor: Istanbul Training and Research Hospital
• Collaborators: Prof. Dr. Cemil Tascıoglu Education and Research Hospital Organization
• Investigators: Principal Investigator: Ufuk Oguz Idiz, Assoc. Prof. MD., Istanbul Training and Research Hospital; Principal Investigator: Eyup Kaya, MD, Prof. Dr. Cemil Tascıoglu Education and Research Hospital Organization

Publications and helpful links

General Publications

• Sasidharan Nair V, Toor SM, Taha RZ, Shaath H, Elkord E. DNA methylation and repressive histones in the promoters of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, PD-L1, and galectin-9 genes in human colorectal cancer. Clin Epigenetics. 2018 Aug 6;10(1):104. doi: 10.1186/s13148-018-0539-3.
• Nakano M, Ito M, Tanaka R, Yamaguchi K, Ariyama H, Mitsugi K, Yoshihiro T, Ohmura H, Tsuruta N, Hanamura F, Sagara K, Okumura Y, Nio K, Tsuchihashi K, Arita S, Kusaba H, Akashi K, Baba E. PD-1+ TIM-3+ T cells in malignant ascites predict prognosis of gastrointestinal cancer. Cancer Sci. 2018 Sep;109(9):2986-2992. doi: 10.1111/cas.13723.
• Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677-704. doi: 10.1146/annurev.immunol.26.021607.090331.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2020
• Primary Completion (Actual): January 1, 2022
• Study Completion (Actual): January 1, 2022

Study Registration Dates

• First Submitted: September 22, 2020
• First Submitted That Met QC Criteria: September 22, 2020
• First Posted (Actual): September 28, 2020

Study Record Updates

• Last Update Posted (Estimate): December 6, 2022
• Last Update Submitted That Met QC Criteria: December 4, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Gastric cancer; Colorectal Cancer; Pancreatic cancer; Immune checkpoints
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Gastrointestinal Diseases; Gastrointestinal Neoplasms
• Other Study ID Numbers: Gastrointestinal checkpoints

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No