T Cells Have the Potential to Reverse Chemotherapy Resistance in Patients With Ovarian Cancer
A new perspective on chemotherapy resistance in ovarian cancer may be a step toward overcoming that resistance. Fibroblasts block chemotherapy, leading to chemotherapy resistance for nearly every woman with ovarian cancer. However, immune system T cells can reverse that resistance. This research suggests that immunotherapy drugs have the potential to treat ovarian cancer.1
"Ovarian cancer is often diagnosed at late stages, so chemotherapy is a key part of treatment. Most patients will respond to it at first, but everybody develops chemoresistance. And that's when ovarian cancer becomes deadly," said J. Rebecca Liu, MD, associate professor of obstetrics and gynecology at the University of Michigan in Ann Arbor, and a co-author of the study.
"In the past, we've thought the resistance was caused by genetic changes in tumor cells. But we found that's not the whole story," she said.
This study analyzed tissue samples from patients with ovarian cancer by separating the cells by type to study the tumor microenvironment. The microenvironment was examined both in cells and in mice, then the findings were linked to actual patient outcomes.
Typically, cisplatin, a platinum-based chemotherapy, is used to treat ovarian cancer. This study found that platinum is blocked by fibroblasts, which prevented the platinum from accumulating in the tumor and protected tumor cells from being killed off by the agent.
In contrast, the researchers found that immune T cells overcame the protection of the fibroblasts. When T cells were added to the fibroblasts, the tumor cells died off.
"T cells are the soldiers of the immune system. We already know that if you have a lot of T cells in a tumor, you have better outcomes. Now we see that the immune system can also impact chemotherapy resistance," said Weiping Zou, MD, PhD, Charles B. de Nancrede Professor of Surgery, Immunology and Biology at the University of Michigan, a co-author of the study.
The researchers boosted the T cells and were able to overcome chemotherapy resistance in mouse models. They did this with interferon, a small protein that manipulated the pathways involved in cisplatin.
Combining chemotherapy with immunotherapy may be effective against ovarian cancer, the researchers suggested. Although inhibitors of the PD-L1 and PD-1 pathway are FDA-approved for the treatment of some cancers, they are not currently approved for the treatment of ovarian cancer.
"We can imagine re-educating the fibroblasts and tumor cells with immune T cells after chemoresistance develops," Zou said.
"Then we could potentially go back to the same chemotherapy drug that we thought the patient was resistant to. Only now we have reversed that and it's effective again," Liu added.
1. Wang W, Kryczek I, Dostal L, et al. Effector T cells abrogate stroma-mediated chemoresistance in ovarian cancer. Cell. 2016;165(5):1092-1105.