MUC1‑induced immunosuppression in colon cancer can be reversed by blocking the PD1/PDL1 signaling pathway

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.

Mucin 1 downregulation decreases the anti-tumor effects of melanoma vaccine

“…Modulation of MUC1 expression affects the immunogenicit y of anticancer vaccines and their antitumor effects. In normal cells, large amou nt s of M UC1 sugar chains prevent t he presentat ion of ant igen ic pept ides and h inder t he proximit y of CTLs, thereby avoiding the k illing of autologous cells by CTLs (14)(15)(16). However, MUC1 has emerged as a novel glycopeptide epitope due to its configuration change, loss of steric hindrance in tumor cells, and easy exposure to immune cells.…”

“…It was also found that the PD-1 and PD-L1 expressed highly in MUC1-positive colon cancer cells, which suggested that there was the positive correlation between the expressions MUC1 and PD-1. It is very promising to apply immunotherapy for targeting the PD-L1/PD-1 signaling pathway in MUC1positive cancer (14)(15)(16). Our previous report showed that the immunogenicity of colon cancer vaccines significantly correlates with MUC1 expression level (13).…”

The Cancer Cell Dissemination Machinery as an Immunosuppressive Niche: A New Obstacle Towards the Era of Cancer Immunotherapy

“…For example, TAMs from renal cell carcinoma patients induce the skewing of autologous blood derived CD4 + T cells towards an exhausted phenotype, with decreased production of effector cytokines and enhanced expression of PD1 and TIM3 (281). Of all immune checkpoint pathways mentioned above, the prominent expression of PDL1, a ligand for PD1, and B7-H4, a ligand for CTLA4, are perhaps the most well-known immunosuppressive mechanisms leading to macrophage-driven T cell exhaustion (282)(283)(284)(285)(286). Of particular interest is the fact that ligands for immune checkpoint receptors are mostly expressed by M2-like macrophages, which are also integral components of TMEM doorways, providing another attractive theory for immune evasion by the migratory/invasive cancer cell subpopulation within the dissemination trajectories.…”

Mucin in cancer: a stealth cloak for cancer cells

“…Anti-cancer immunity is frequently suppressed by oncogenic signals. MUC1 causes immunosuppression in CRC ( 52 ) and induces T-cell tolerance in vivo ( 53 ). Additionally, apoptosis activating pathway defects such as masking of death receptor ( 54 ) and attenuated cytochrome c releasing and caspase-3 activation ( 55 ) are led by MUC1.…”