It's Hot or it's Cold: Pancreatic Tumors and Immunotherapy Response.
Posted by Leanne Kodsman on
One of the most deadly and difficult-to-treat cancers, pancreatic cancer often results in tumors that are either filled with T-cells (making them "hot"), or containing few T-cells (making them "cold"). This variance can impact the effectiveness of immunotherapy, and researchers are looking at ways to control a pancreatic tumor's "temperature" to increase the cancer's responsiveness to immunotherapy.
Pancreatic cancer is one of the leading causes of cancer death and is notoriously hard to treat. One of the reasons that treatment is so difficult is that pancreatic tumors can vary in heterogeneity, running "hot" (meaning they are filled with T cells) or "cold" (containing fewer T cells, making them less sensitive to immunotherapy). New research looks at how pancreatic tumors become hot or cold, and whether the tumor's "temperature" can be controlled to make immunotherapy more effective.
The research team experimented with a range of pancreatic cancer cell clones, implanting them into immunocompetent mice. The scientists found that tumor-cell-intrinsic factors not only shape the immune microenvironment in the tumor, but also impact the outcome of immunotherapy treatments.
The team implanted different pancreatic cancer cell lines into mice, growing tumors that became either hot or cold. The tumor's temperature (T cell concentration), the researchers found, played a role in whether the cancer would respond to immunotherapy.
The mice were treated with a checkpoint blockade drug, or a checkpoint blockade drug along with either an anti-DC40 agonist, chemotherapy, or both. The mice with hot tumors who underwent treatment saw tumor regressions, and the mice with hot tumors who were treated with chemo- and immunotherapy saw a durable response to the treatment. The mice with cold tumors, however, did not clear their cancer with any of the therapies.
Once they had determined that tumor temperature was tied to treatment success, the team wanted to look closely at the cold tumors to determine whether there was a molecular basis for these results. The cold tumor cells, they found, made a compound called CXCL1.
CXCL1 signals myeloid cells to enter the tumor, while simultaneously signaling T cells to stay away. The researchers found that this response is what kept the tumor cold, and therefore unresponsive to immunotherapy.
When the scientists targeted the CXCL1 in the cold tumors, they found that eliminating the tumor's CXCL1 would promote T cell infiltration. Once this happened, the tumors became responsive to immunotherapy.
Other studies have shown that T cell "attraction" in a tumor is regulated by the tumor's genetic makeup. Every tumor is unique, so future research is expected to look at finding ways to use a tumor's biological makeup to help increase the success of treatment.
Further Reading & References:
GEN: Genetic Engineering & Biotechnology News. Pancreatic Tumors Run Hot, Cold Depending on Tumor-Cell-Intrinsic Factors. June 29 2018.
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