The Power and Potential of the Microenvironment in Cancer Metastasis
Although genetic — including epigenetic — alterations are the driving events in cancer, the tumor microenvironment, referring to the cellular and molecular changes in non-cancer cells and tissues, are altered during cancer progression. The microenvironment is involved in multiple aspect of cancer progression. Tumor metastasis is a critical step in the progression of solid tumors that is associated with patient mortality, and the metastatic microenvironment is a key regulator of this process. The pre-metastatic niche is the microenvironment important for metastatic initiation that is established at distant sites in response to primary tumor factors during cancer progression.
We characterized this microenvironment in the metastatic sites of tumor-bearing mice. We have identified unique changes and in these pre-metastatic sites by flow cytometry and RNA sequencing approaches. We identified a gene signature in pre-metastatic niche formation that demonstrates upregulation of immune suppression genes that is consistent across different metastatic tissue, including lung and liver, as well as across species with commonalities in murine and human early metastatic microenvironments. Performing single cell RNA sequencing of the pre-metastatic niche revealed key immune suppressive genes were found in the myeloid cell clusters. In addition to the increase of myeloid cells and immunosuppressive pathways, we discovered that T cell populations are reduced in pre-metastatic lungs. We hypothesized that reversing this immunosuppressive environment would restore T cell function and antitumor immunity. We designed a novel approach in which we generated Genetically-Engineered Myeloid cells (GEMys) to deliver IL-12, a potent antitumor molecule, into the pre-metastatic microenvironment.
Our studies demonstrate that IL12-GEMys can functionally modulate the core program of immune suppression in the pre-metastatic niche to successfully rebalance the dysregulated metastatic microenvironment in cancer. Therapies harnessing the power of the tumor microenvironment to modulate cancer progression can hold promise to effectively limit metastatic progression.
This page was last updated on Friday, February 3, 2023