11:35pm Tuesday 14 July 2020

Weill Cornell Investigators Discover How Ovarian Cancer Halts Body's Natural Defense Against Tumor

NEW YORK  — Ovarian cancer shuts down immune system cells that would otherwise act as a first line of defense against the deadly tumor, Weill Cornell Medical College scientists report today. But a therapy that restores the cells’ disease-fighting abilities could provide a powerful new strategy to attack the cancer, which kills more than 14,000 women each year.

In the June 11 issue of Cell, the investigators identify a gene in dendritic cells that ovarian cancer turns on, resulting in the cells’ inability to mount an effective response against the tumor. In preclinical studies, they demonstrate that turning off the gene, XBP1, restores dendritic cell function and triggers robust immune responses against ovarian tumors.

“The high death rate in ovarian cancer has remained the same over the last 40 years because there have been no new therapeutic strategies. This study offers us a new approach — a bright beacon of hope,” says senior author Dr. Laurie H. Glimcher, the Stephen and Suzanne Weiss Dean of Weill Cornell Medical College and a researcher in its Sandra and Edward Meyer Cancer Center.

“Harnessing the natural ability of our immune system to eliminate malignant cells represents the most promising anti-ovarian cancer strategy since the development of chemotherapy,” she adds. “We look forward to developing new ways to unleash protective immune responses in ovarian cancer.”

Dr. Laurie H. Glimcher
Photo credit: Lisa Berg

The findings extend the Glimcher lab’s discovery that XBP1 is a potential Achilles’ heel in cancer. Investigators there reported last year that the gene plays a key role in the development and progression of the triple negative form of breast cancer, a lethal tumor that’s especially difficult to treat. Because of XBP1’s ability to promote tumor cell survival, the group suspected it could also play a role as an inhibitor of anti-tumor immunity.

The gene is part of the endoplasmic reticulum stress response pathway — also called the unfolded protein response — that can allow tumors to grow and survive when they are deprived of nutrients and oxygen.

But ovarian cancer, in its advanced form, is not like breast cancer. It is solid like breast cancer in its earliest stages, but as it grows into the confines of the peritoneal cavity, which encases organs within the abdominal cavity, it becomes soup-like. Nearly 75 percent of ovarian cancers are discovered at this late stage.

Floating in this broth is a mash of cancer cells, dendritic cells, and other immune cells that make up the tumor microenvironment. Because it is in contact with other organs within the abdomen, the cancer can easily spread.

Dr. Juan Cubillos-Ruiz
Photo credit: Carlos Rene Perez

Analyzing human patient specimens and samples from preclinical models of disease, Dr. Glimcher and her team found that ovarian cancer promoted a tumor microenvironment full of toxic, reactive oxygen molecules that modified proteins located in the endoplasmic reticulum. This, in turn, induced XBP1 activation and produced a buildup of lipid molecules within the dendritic cells contained in the soup.

While that kept dendritic cells healthy, XBP1 also switched on genes that block their ability to stimulate other immune cells, says lead author Dr. Juan R. Cubillos-Ruiz, an instructor of microbiology and immunology in medicine at Weill Cornell. “Dendritic cells normally take an antigen — a bit of cancer cell — and show it to other immune cells called T cells. This crucial process enables T cells to eliminate tumors,” he says.

This is the first time scientists have found that XBP1 can co-opt and turn off immune cell function in cancer. “We are now devising first-in-class drugs that can inhibit the activity of XBP1 in both cancer cells and dendritic cells, which would both sensitize the cancer to treatment and restore an immune response against it,” Dr. Cubillos-Ruiz says. Apart from some experimental studies, ovarian cancer is not treated with immunotherapy.

This image, featuring the underdog, the large dog and the prize, illustrates the Cell study through the lens of an analogy. The immune system, represented here as an underdog, a mutt, is cowering in front of the menacing XBP1 dog. At the end of the pathway, where the immune system dog aims to reach, is the tumor. This tumor, represented by a large steak, is all the immune system wants to get to, but the small dog is being suppressed by the lack of know-how to get around the XBP1 dog.
Image credit: Sam Spaeth

In the study, the scientists tested a strategy in which mice were injected with nanoparticles, microscopic polymers that carry a genetic molecule that can silence the XPB1 gene. Dendritic cells detect the nanoparticles as invaders, and ingest them. Once inside, the nanoparticles — developed by Dr. Cubillos-Ruiz — deliver the molecule that turns XBP1 off, allowing dendritic cells to tell the immune system to attack the cancer. “The nanoparticles act like a Trojan Horse, releasing the payload that will turn XBP1 off,” Dr. Cubillos-Ruiz says.

“Immune-based approaches have succeeded in other lethal cancers, such as melanoma, and it may be very beneficial as well in ovarian cancer,” Dr. Glimcher says. “Our study shows that XBP1 activation in dendritic cells drives both primary and metastatic ovarian cancer progression. We believe that targeting XBP1 should both inhibit tumor growth and enhance anti-cancer immunity.”

Study co-authors are, from Weill Cornell Medical College: Pedro C. Silberman, Sahil Chopra, Minkyung Song, Divya Gupta, Kevin Holcomb, Thomas Caputo, Lora H. Ellenson, Sarah Bettigole and Ann-Hwee Lee; Melanie R. Rutkowski, Alfredo Perales- Puchalt and Jose R. Conejo-Garcia from The Wistar Institute in Philadelphia; and Sheng Zhang from Cornell University in Ithaca.

This study was supported by NIH grants R01CA112663, R01CA157664, R01CA124515 and 1S10RR025449-01, as well as the Irvington Institute Fellowship Program of the Cancer Research Institute and the Fundación Alfonso Martín Escudero.

Weill Cornell Medical College

Weill Cornell Medical College, Cornell University’s medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances — including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson’s disease, and most recently, the world’s first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with Houston Methodist. For more information, visit weill.cornell.edu.

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