MUC1-induced immunosuppression in colon cancer can be reversed by blocking the PD1/PDL1 signaling pathway
Yinghui Zhang1, Xiangqian Dong2, Liping Bai1
1Department of Gastroenterology, The Fourth Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650021, P.R. China.
Abstract:
Mucin1 (MUC1) upregulation in colon cancer has been linked to poor patient outcomes and advanced stage at diagnosis. This is partially due to MUC1-mediated inhibition of T-cell proliferation affecting efficient lysis by cytotoxic lymphocytes, which contributes to escape from immune surveillance. In the present study, human colorectal cancer tissues were collected, and MUC1-positive and MUC1-negative colon cancer mouse models were prepared; subsequently, the number and function of immune cells in tumor tissues were measured using flow cytometry. The present study revealed that MUC1, as a tumor-associated antigen, can recruit more tumor-infiltrating lymphocytes into the tumor microenvironment compared with MUC1-negative colon cancer, but that these cells could not serve antitumor roles. Conversely, the present study demonstrated that MUC1-positive colon cancer attracted more regulatory T cells (Treg cells), myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) to the tumor site than MUC1-negative colon cancer. Furthermore, the data suggested that programmed death protein 1 (PD1)-programmed death ligand 1 (PDL1) expression is greater in MUC1-positive colon cancer. Blocking the PD1-PDL1 signaling pathway reduced the percentage of Treg cells, MDSCs and TAMs in the tumor microenvironment, enhanced T-cell cytotoxicity and inhibited tumor growth, prolonging the survival time of MUC1-positive tumor-bearing mice. Therefore, the present study elucidated the role of MUC1 in tumor immune escape and provides a foundation for the application of PDL1 inhibitors to MUC1-positive colon cancer.
Insights
Mucin1 (MUC1) promotes colon cancer immune escape by increasing suppressive immune cells and PD-L1 expression. Blocking PD-1/PD-L1 signaling reverses this, enhancing anti-tumor immunity and survival in MUC1-positive tumors.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Mucin1 (MUC1) upregulation correlates with poor outcomes in colon cancer.
- MUC1 contributes to immune evasion by inhibiting T-cell responses.
Purpose of the Study:
- To investigate MUC1's role in the tumor immune microenvironment and its impact on immune escape.
- To evaluate the therapeutic potential of PD-1/PD-L1 pathway blockade in MUC1-positive colon cancer.
Main Methods:
- Analysis of human colorectal cancer tissues.
- Creation and assessment of MUC1-positive and MUC1-negative mouse models.
- Flow cytometry to quantify immune cell populations and function.
- Evaluation of PD-1/PD-L1 pathway blockade efficacy.
Main Results:
- MUC1-positive tumors recruit more tumor-infiltrating lymphocytes but also more suppressive cells (Tregs, MDSCs, TAMs).
- MUC1-positive tumors exhibit higher PD-1/PD-L1 expression.
- PD-1/PD-L1 blockade reduced suppressive cells, enhanced T-cell cytotoxicity, and inhibited tumor growth.
Conclusions:
- MUC1 plays a critical role in colon cancer immune evasion.
- Targeting the PD-1/PD-L1 pathway is a promising strategy for MUC1-positive colon cancer.
