Ovarian cancer: Immunotherapy may overcome chemotherapy resistance

Ovarian cancer is often diagnosed when it is at an advanced stage, so chemotherapy is a key part of treatment. However, the cancer eventually develops resistance to chemotherapy - a major reason for its low survival rate. Now, new research suggests it may be possible to overcome chemotherapy resistance in ovarian cancer by adding immunotherapy to the chemotherapy.

In the journal Cell, researchers from the University of Michigan in Ann Arbor describe how they reversed chemotherapy resistance in mouse models of ovarian cancer by boosting the animals' immune T cells.

The team suggests the finding will prompt a re-think about chemotherapy resistance in ovarian cancer and could lead to new treatments using immunotherapy.

Ovarian cancer is one of the five main types of cancer that affect a woman's reproductive organs. The other four are: cervical, uterine, vaginal, and vulvar cancer.

Ovarian cancer is typically treated with a platinum-based chemotherapy called cisplatin, which causes platinum to build up inside the nucleus of cancer cells. The platinum damages the cancer cells' DNA and stops them dividing.

For their study, co-senior author J. Rebecca Liu, associate professor of obstetrics and gynecology, and colleagues used tissue samples from patients with ovarian cancer and also mouse models of the disease to study the types of cell in the microenvironment of tumors. They linked the results back to patient outcomes.

Their results highlight the role of two types of cell: fibroblasts and immune T cells. Fibroblasts are cells that generate the connective tissue (the stroma) that supports cells. Immune T cells are the foot soldiers of the immune system and researchers have already shown that their high presence in tumors favors patient outcomes.

The researchers found that fibroblasts help ovarian cancer cells become resistant to cisplatin, and immune T cells work against this effect.

Immune system can affect chemotherapy resistance

In their study Prof. Liu and colleagues show that fibroblasts prevent platinum from building up in the ovarian tumor cells, resulting in resistance to cisplatin and survival of the cancer cells.

Specifically, they demonstrate how two compounds released by the fibroblasts - glutathione and cysteine - contribute to this resistance.

However, when they added immune T cells to the fibroblasts, the tumor cells began to die off, showing that the immune system can affect chemotherapy resistance.

The researchers note that the "T cells abolish the resistance by altering glutathione and cystine metabolism in fibroblasts." (Note that cysteine and cystine are two different, but related, molecules in this situation).

They found that interferon - a small protein that is released by the immune T cells - controls fibroblast glutathione and cysteine via a particular signaling pathway.

Linking the findings back to patient outcomes, the team found that the presence of stromal fibroblasts is linked to lower patient survival, while the presence of immune T cells is linked to higher patient survival.

The results lead the authors to suggest that using this interplay between chemotherapy and immunotherapy "holds high potential for cancer treatment."

They can see how it may be possible to use immune T cells to alter the behavior of the fibroblasts after chemoresistance develops. Thus, it should be possible to return to the same chemotherapy drug that the patient had become resistant to, after immunotherapy has restored its effectiveness.

"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."

Prof. J. Rebecca Liu

Drug regulators in the U.S. have just approved an immunotherapy drug to treat bladder cancer.