A better understanding of the function of non-cancerous cells and tissue surrounding colon cancer cells is providing a clearer picture of how the immune system recognizes and accesses the cancer site, according to a new study by University of Wisconsin Carbone Cancer Center (UWCCC) researchers.

The study found a biomarker in the tumor microenvironment, the matrix surrounding the cancer, which may better predict which patients will benefit from immunotherapies and could serve as a drug target for others.

The five-year survival rate for metastatic colorectal cancer (CRC) patients is only 12 percent, a rate Dr. Dusty Deming, a physician-researcher who specializes in CRC, calls “unacceptably low.” He said that improving immune cell access to tumor sites has been a priority of the National Cancer Institute and CRC physicians for some time now.

Dusty Demin and Fotis Asimakopoulos in the lab
Dusty Deming (left) and Fotis Asimakopoulos collaborated on the study.

“Cancers that have infiltration of immune system T cells have a better prognosis, earlier stage and they potentially do better with immunotherapies,” Deming said. “To understand who might benefit from immunotherapies, we need to know what controls the immune microenvironment and what controls the infiltration of T cells, and this study is a big step in that direction.”

Just a few floors away from Deming, UWCCC hematologist and researcher Dr. Fotis Asimakopoulos and his lab group had recently shown that, when present, the protein versikine in the myeloma tumor microenvironment helped recruit and train T cells. Versikine is generated from the matrix processing of its parent protein, versican.

“Cancers have been characterized as wounds that do not heal, and versican contributes to this condition by accumulating at cancer sites, sustaining inflammation and blocking the immune system from fighting the cancer,” Asimakopoulos said. “Versican’s processing into versikine does the opposite in myelomas.”

Because CRCs are associated with chronic inflammation, Deming and Asimakopoulos joined forces to see if there was overlap between the behavior of the myeloma and CRC tumor microenvironments.

Using 122 CRC samples acquired by the UWCCC BioBank, Deming, Asimakopoulos and colleagues first stained them for the presence of versican and versikine. They found that the cancerous regions had higher levels of versican, but healthy surrounding tissue had higher levels of versikine. Next, they stained samples for T cells, and found that if versikine levels were high in the tumor, then T cell infiltration into the tumor site was also high.

To move their findings further into clinical relevance, the researchers also needed to know if it was coincidence that high versikine levels were associated with T cell infiltration, or if the processing of versican into versikine actually boosted the T cell numbers at the cancer sites. So next they treated cultured bone marrow cells, the precursors to immune cells, with versikine. They looked to see which immune cells increased in number, and found that a class of cells known as Batf3 dendritic cells was enriched.

“This subset of dendritic cells is key for the success of all the immunotherapies that we commonly talk about, and these cells both educate the T cells by showing them the tumor antigens and invite the T cells into the tumor,” Asimakopoulos said. “We found a way by which their differentiation into this class of dendritic cells is affected by the tumor matrix.” 

Deming said this work provides opportunities for research to improve patient outcomes moving forward.

“We’re excited about versikine as a biomarker to identify those patients for whom an immunotherapy strategy is best,” Deming said. “Also, can we manipulate this pathway that converts versican to versikine to enhance tumor responses to immunotherapies?”

Asimakopoulos added that these findings highlight a need to further study the tumor matrix to better understand and treat cancers.

“Every tumor has a matrix, and the matrix is a living, dynamic structure that responds to the needs of the physiology of the growing tumor; sometimes it works against the tumor, sometimes it enables tumor growth,” Asimakopoulos said. “We need to understand how the matrix influences tumor behavior so that we can find ways to make this immunotherapy revolution applicable to more patients.”

Deming and Asimakopoulos were co-senior authors of the study, which was recently published in the Journal of Immunology. It was funded in part by the UWCCC Core Grant (NIH P30CA014520), the American Cancer Society (RS-15-01-LIB), and a V Foundation Scholar award, as well as UWCCC’s Trillium Fund, Funk Out Cancer, Bowlin’ for Colons, and the Cathy Wingert Colorectal Cancer Research Fund.