Track topics on Twitter Track topics that are important to you
Immune checkpoint inhibitors have shown clinical benefit in several cancer entities including metastatic microsatellite instable colorectal carcinomas. However, for the majority of metastatic colorectal carcinomas the potential and limitations of immune checkpoint inhibition is not fully understood. In this study, the effects of sole and dual CTLA-4 and PD-L1 blockade were investigated in a microsatellite stable highly aggressive orthotopic mouse model of colon cancer. Dual CTLA-4 and PD-L1 inhibition resulted in tumor growth stagnation and completely blocked liver metastasis. Sole CTLA-4 and PD-L1 inhibition only moderately reduced metastatic spread of the colon cancer cells, though CTLA-4 blockade being superior to PD-L1 inhibition. Dual immune checkpoint blockade and sole CTLA-4 inhibition significantly increased intratumoral CD8+ and CD4+ T cells and reduced FOXP3+/CD4+ Treg cells. This was associated with increased expression levels of the pro-inflammatory Th1/M1-related cytokines IFN-γ, IL-1α, IL-2, and IL-12. Moreover, tumors treated with combined immune checkpoint blockade showed the strongest increase in intratumoral iNOS+ macrophages, reduction of PD-L1+ and Tie2+ macrophages and the lowest expression of M2/Th2-related IL-4, TARC and COX-2. The assessment of further microenvironmental changes by DCE-MRI and immunohistology revealed no alterations in functional tumor vascularization upon combined immune checkpoint blockade, but a significant increase in intratumoral fibroblasts and collagen I deposition. Thus, the synergistic inhibitory effects of dual immune checkpoint inhibition can be explained by anti-tumorigenic T cell responses mediated by CTLA-4 inhibition and M1 macrophage polarization predominantly induced by PD-L1 blockade. This was accompanied by pronounced fibroblast activation highlighting the interconnection between immunogenicity and desmoplasia.
This article was published in the following journal.
Name: Neoplasia (New York, N.Y.)
The system of hepatocyte growth factor (HGF) and its receptor c-Met plays a critical role in tumor invasive growth and metastasis. The mortality rate of colorectal cancer (CRC), one of the most common...
Liver cancer is a leading cause of cancer-related deaths globally. Tumor response rate of liver cancer patients towards systemic chemotherapy is low and chemoresistance can easily develop. Identifying...
Cancer cells harness immune checkpoints such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and indoleamine 2,3-dioxygenase 1 (IDO1) to evade immune co...
Primary gastric cancer (PGC) is the fourth most common malignant human cancer and the second leading cause of death worldwide. The majority of the subjects of PGC is diagnosed at a late stage, resulti...
PD-L1 on the surface of tumor cells binds its receptor PD-1 on effector T cells, thereby suppressing their activity. Antibody blockade of PD-L1 can activate an anti-tumor immune response leading to d...
Surgical resection is still recommended as the optional treatment for colorectal liver metastasis (CLM) patients. There are two main concerns for resectable colorectal liver metastasis whi...
This is an open-label, non-randomized, single-institution, single arm Phase II study conducted using a Simon two-stage design with an additional safety lead-in. The overall objective is to...
This is a single-arm, open-label, one center clinical study, to determine the safety and efficacy of infusion of autologous T cells engineered to express immune checkpoint antibodies (CTLA...
This prospective database has two main objectives; - to evaluate the complication rates, 30-day and 90-day mortality from different surgical strategies for unresectable, borderlin...
The standard treatment of unresectable liver metastasis in gastrointestinal tract cancer is chemotherapy, but considerable portion of the patients progressed and most of the liver is conve...
An anti-CTLA-4 ANTIGEN monoclonal antibody initially indicated for the treatment of certain types of metastatic MELANOMA. Its mode of actions may include blocking of CTLA-4 mediated inhibition of CYTOTOXIC T LYMPHOCYTES, allowing for more efficient destruction of target tumor cells.
Hypoxic conditions in tumor cells due to the tumor outgrowing its blood supply. It is associated with increased METASTASIS and resistance to RADIOTHERAPY and DRUG THERAPY.
A malignant tumor composed of cells showing differentiation toward sebaceous epithelium. The tumor is solitary, firm, somewhat raised, more or less translucent, and covered with normal or slightly verrucose epidermis. It may be yellow or orange. The face and scalp are the commonest sites. The growth can be slow or rapid but metastasis is uncommon. Surgery cures most of the cases. (From Rook et al., Textbook of Dermatology, 4th ed, pp2403-4)
An extracellular matrix glycoprotein from platelets and a variety of normal and transformed cells of both mesenchymal and epithelial origin. Thrombospondin-1 is believed to play a role in cell migration and proliferation, during embryogenesis and wound repair. Also, it has been studied for its use as a potential regulator of tumor growth and metastasis.
Proteins whose abnormal expression (gain or loss) are associated with the development, growth, or progression of NEOPLASMS. Some neoplasm proteins are tumor antigens (ANTIGENS, NEOPLASM), i.e. they induce an immune reaction to their tumor. Many neoplasm proteins have been characterized and are used as tumor markers (TUMOR MARKERS, BIOLOGICAL) when they are detectable in cells and body fluids as monitors for the presence or growth of tumors. Abnormal expression of ONCOGENE PROTEINS is involved in neoplastic transformation, whereas the loss of expression of TUMOR SUPPRESSOR PROTEINS is involved with the loss of growth control and progression of the neoplasm.
Hepatology is the study of liver, gallbladder, biliary tree, and pancreas, and diseases associated with them. This includes viral hepatitis, alcohol damage, cirrhosis and cancer. As modern lifestyles change, with alcoholism and cancer becoming more promi...
Colon or Colorectal cancer is the growth of malignant polyps on the colon, bowel, anus and rectum. Growths in these locations can be benign, and removed by colonoscopy, but they have a risk of becoming malignant. About 10 per cent of bowel cancer...
Cancer is not just one disease but many diseases. There are more than 100 different types of cancer. Most cancers are named for the organ or type of cell in which they start - for example, cancer that begins in the colon is called colon cancer; cancer th...