The prognosis of most cancer patients depends on the extent of primary tumor metastasis to distant organs. At the time of diagnosis a substantial percentage of patients with colorectal carcinoma have already developed liver metastases. Many patients who are free of liver metastases can be saved by surgical resection of the primary tumor, however, surgery itself can enhance metastasis development in the liver. Circulating tumor cells in the liver sinusoids interact with various resident immune cells in the liver such as Kupffer cells, iNKT cells and neutrophils. This interaction results in weak immunity against tumor cells due to the tolerant environment in the liver which promotes the establishment of metastases.
We hypothesized that adjuvant immunotherapy could stimulate liver resident effector cells to attack tumor cells thereby restricting their survival and lowering the occurrence of hepatic metastases.
We found that monoclonal antibody therapy targeting tumor cells stimulates Kupffer cells to phagocytose cancer cells and impedes the formation of liver metastases. However, Kupffer cells lack the ability to reduce established metastases. In a different approach we used a strong iNKT cell agonist (α-GalCer) to stimulate the secretion of immunomodulatory cytokines in the liver. iNKT cells created a tumor hostile hepatic microenvironment that led to reduced tumor growth and increased the survival rate. Yet, continuous treatment with the iNKT cell agonist attenuated the anti-tumor effect and enhanced the incidence of metastases indicating that α-GalCer therapy is only effective within a narrow temporal window. Lastly, the engagement of circulating neutrophils by therapeutic antibodies in combination with innate immune checkpoint inhibition demonstrated that neutrophils have anti-tumor activity in the presence of therapeutic antibodies in the liver.
These studies demonstrated that adjuvant immunotherapy can delay the formation of liver metastases but they also indicated that the start point and duration of treatment are critical factors and that anti-metastatic therapy is only effective within a narrow window.