Scientists Engineer Immune Cells with Cytokine to Stop Cancer Spread

One of the biggest hurdles in curing cancer is to prevent its spread to secondary sites (metastasis) and relapse. Improving the tumor microenvironment is an effective strategy to enhance tumor clearance. Addressing these two aspects, a team of scientists from the National Cancer Institute at NIH developed a new approach to immunotherapy to ‘prime’ organs to resist cancer spread.

New Study

In a new study published in Cell, authors investigated the immune repertoire in premetastatic organs, possible sites where cancer is likely to spread, and found that a type of immune cells called myeloid cells causes immune suppression and promotes metastasis in this niche. Strikingly, redesigning the myeloid cells to deliver anti-cancer drugs improves the immunogenicity of the premetastatic niche to fight the cancer.

Several studies show that there is an abundance of differentiated myeloid cells in specific organs, which are likely sites of metastasis. This indicates that the immune system can recognize the onset of metastasis and prepares these sites with its first line of defense. However, these myeloid cells suppress the immune response by limiting inflammation and activation of T cells and hence facilitate cancer spread. Previous studies by lead author Dr. Rosandra Kaplan discovered that these ‘premetastatic niches’ are made ready for cancer due to their unique myeloid cell population. Hence, they hypothesized that re-engineering the myeloid cells in the niche to deliver cytokines and activating the immune response could prevent metastasis.

Using a mouse model with rhabdomyosarcoma- a pediatric cancer of the muscle which spontaneously metastasizes to the lungs, the researchers analyzed the immune cell populations in the premetastatic lungs and found an enrichment of myeloid cell populations and reduction in dendritic cells, CD4+ T cells which promote immune suppression. Comparison of lung tissue from naïve and pre-metastatic mice showed that there was a dramatic shift in transcriptional program and upregulation of myeloid cells due to the tumor, demonstrating that adaptive immunity is turned off in the premetastatic niche.

Genetically-Engineered Myeloid Cells (GEMys)

Next, the team designed genetically-engineered myeloid cells- ‘GEMys’ to deliver immune activators to the pre-metastatic niche. Given that myeloid cells infiltrate the tumor and metastatic environments, GEMys with IL-12 cytokine restored T-cell activation and dendritic cell population in the premetastatic lungs, promoted pro-inflammatory cells, and hence reversed the immune suppression. Tumor mice treated with IL12-GEMys had reduced metastasis in the lungs and improved survival. The results were reproduced in a pancreatic cancer model of mice where IL12-GEMys reduced metastasis to the liver.

With further plans of clinical trials in adults, Dr.Kaplan said, “this is a novel approach to immunotherapy that appears to have promise as a potential treatment for metastatic cancer. We were excited to see that the GEMys ‘changed the conversation’ in the premetastatic niche. They were now telling other immune cells to get ready to fight the cancer.”

A combination of chemotherapy with GEMys is likely to effectively fight cancer and metastasis, as evidenced by no tumor formation upon injecting tumor cells in mice cured by the combination therapy. The authors also synthesized GEMys from human cells and found similar improvements in inflammatory response in human cell lines.

The GEMys need to be validated for their safety and similar homing mechanism in humans. However, the study shows promise in identifying the mechanism of metastasis and preventing it. The dose of IL-2 cargo in the GEMys is small, and GEMys do not multiply in the body to cause IL-2 toxicity. These factors reassure the authors that IL-12 GEMys can be further developed for cell therapy against a wide variety of cancers.

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Author

Sahana Shankar