Study shows PARP inhibitor drugs rouse immune system attack on some ovarian cancers

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Drugs known as PARP inhibitors are transforming the treatment of some ovarian and breast cancers by sabotaging tumor cells’ ability to keep their DNA in working order. In a new study, scientists at Dana-Farber Cancer Institute report that PARP inhibitors can endanger tumor cells on a second front – by sparking an immune system attack on them.

The discovery, made in mouse models of a common type of ovarian cancer, not only reveals PARP inhibitors to be a double threat to cancer cells, but suggests that combining PARP inhibitors with an immunotherapy agent can extend remissions triggered by the drugs. The study is being published online today by the journal Cell Reports.

“Three PARP inhibitors have been FDA-approved for the treatment of ovarian cancer with mutations in the BRCA genes. These represent the first targeted therapies approved for ovarian cancer, the number one cause of gynecologic cancer-related death,” said the senior author of the new study, Jean Zhao, PhD, of Dana-Farber and the Broad Institute of MIT and Harvard. “The effectiveness of PARP inhibitors in these cancers has been thought to be due entirely to the direct killing of tumor cells. We show that the immune response provoked by the drugs plays a key role in cancer cell death as well.”

PARP inhibitors work by hindering cells’ ability to repair breaks in single strands of their DNA. In cancer cells that are already having difficulty fixing two-stranded breaks – because of a mutation or other abnormality in the BRCA1 or BRCA2 genes – the loss of single-strand repair can be a lethal blow. As DNA damage accumulates, the tumor cells gradually become dysfunctional and destroy themselves for the good of the body.

Scientists recently discovered that the immune system responds to DNA damage in tumor cells during treatment by dispatching powerful agents – including T cells and interferon, a family of proteins that intensifies the immune response – to the site of the tumor. This immunological show of force was generally thought to pose no threat to the tumor cells: scientists believed it was largely a response to the die-off of tumor cells instigated by PARP inhibitors, not an attack on the tumor cells themselves. Zhao and her colleagues set out to discover if that is truly the case.

One reason for the uncertainty surrounding the immune response to PARP inhibitors was a lack of animal models in which it could be studied. Co-First author Liya Ding, PhD, a research fellow in Zhao’s lab, cleared that hurdle by engineering two strains of mice that developed high-grade serous ovarian cancer (HGSOC) – the most common form of ovarian cancer – with genetic aberrations like those in human HGSOC. One strain had a normal complement of BRCA1; in the other, the gene was missing.

In the models deficient in BRCA1, researchers found that treatment with PARP inhibitors triggered an immune response that engulfed the tumors with T cells and other immune system agents. “We then asked whether the immune response was meaningful,” Zhao remarks. “Does it inhibit tumor growth or is it mainly a response to the death of tumor cells?”

In a series of experiments, they demonstrated that it is overwhelmingly the former. In one experiment, they disabled T cells known as CD8+ T cells – which directly attack tumor cells – after the animals had been treated with a PARP inhibitor. The result was a regrowth of the ovarian tumors – evidence that CD8+ T cells were active participants in an assault on cancer cells.

They also analyzed the tumor microenvironment – the tissue within and around tumors – and found it to be replete with CD8+ T cells and allied CD4+ cells, along with an upsurge in two types of interferon, which activate the cancer cell-killing weaponry of T cells. Their presence brought an influx of dendritic cells, which help coordinate the immune system attack on cancer. 

The increase in dendritic cells provided a clue to the mechanism by which PARP inhibitors spur an immune response in HGSOC cells with BRCA1 defects. Tumor cells expel broken bits of DNA as if they were jetsam. An enzyme called cGAS binds to these fragments and switches on the STING signaling pathway in dendritic cells, which sends T cells on an anti-tumor mission.

Together, these findings made a strong case that the immune response to PARP inhibitors is more than just a mop-up crew for dead cancer cells but is a partner in killing those cells.

The immunological onslaught triggered by the drugs can often be blunted by tumor cells, however. Zhao and her colleagues found that when HGSOC tumors deficient in BRCA1 are treated with PARP inhibitors, the tumor cells increase their output of PD-L1 – an “immune checkpoint” protein that renders them invisible to the immune system. Drugs known as checkpoint inhibitors are capable of removing the immune system’s blinders so an attack on the tumor can proceed. The researchers found that mice treated with combination of the PARP inhibitor olaparib and an immune checkpoint inhibitor lived longer than those treated with olaparib alone.

“This observation has important implications for the treatment of ovarian cancer,” said Ursula Matulonis, MD, director of Gynecologic Oncology in the Susan F. Smith Center for Women’s Cancers at Dana-Farber and a co-corresponding author of the study. “When combined with other agents such as PD-1 inhibitors, PARP inhibitors can have enhanced anti-cancer activity, and we now know why.  Clinical trials of combined PARP inhibitors and anti-PD-1 have been conducted and are also ongoing at Dana-Farber.”

“The genetically engineered mouse platform developed by Dr. Zhao and her lab will provide a strong foundation for testing future combinations of PARP inhibitors and therapies that boost the immune system.”

The co-first authors of the study, with Liya Ding, are: Hye-Jung Kim, PhD, and Qiwei Wang, PhD, of Dana-Farber. The study co-authors are: Michael Kearns, Tao Jiang, PhD, Carolynn E. Ohlson, PA-C, Ben B. Li, PhD, Shaozhen Xie, PhD, Joyce F. Liu, MD, MPH, Elizabeth H. Stover, MD, PhD, Suzan Lazo, Thomas M. Roberts, PhD, Gordon J. Freeman, PhD, and Panagiotis A. Konstantinopoulos, MD, PhD, of Dana-Farber; and Brooke E. Howitt, MD, and Roderick T. Bronson, DVM, of Brigham and Women’s Hospital.

Funding for the study was provided by: The Friends of Dana-Farber Cancer Institute; a KL2-Catalyst Medical Research Investigator Training Grant from the National Institutes of Health (grant 5KL2TR001100-05); the Ovarian Cancer Research Fund Alliance; the Breast Cancer Research Foundation; the Men’s Collaborative of Dana-Farber Cancer Institute Fund; the Sandra Fishman Research Fund of Dana-Farber Cancer Institute; and the National Institutes of Health/National Cancer Institute (grants P01 AI056299, P50 CA101942, CA187918, and CA210057).

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