- Young investigators at Dana-Farber are working to understand why tumors may be resistant to T-cell immunotherapy, and to identify novel targets for immunotherapy.
- They are also testing the potential of ovarian organoids — minuscule spheres of cells that mimic a tumor — to rapidly screen drugs and identify those that are likely to be effective against a specific patient’s tumor.
In their search for better treatments for breast, ovarian, and other cancers, young investigators Jennifer Guerriero, PhD, and Sarah Hill, MD, PhD, rely on a precious commodity — patient tissue samples obtained by surgeons in Dana-Farber’s Susan F. Smith Center for Women’s Cancers.
Studies of these normal and cancerous tissues, which are collected, banked, and grown in the laboratory, are helping researchers understand why tumors are vulnerable to certain drugs and resist others. Examination of the microenvironment of the tumor cells (that is, the matrix of connective tissue and various types of cells interacting with the tumor cells) is shedding light on the role of immune cells surrounding the tumor; some of those cells can suppress an attack on the cancer, while others can fuel the attack.
“[This is] an amazing opportunity to work with world-renowned scientists and clinicians at Dana-Farber and to bridge the basic and translational science we’re doing in the lab using clinical samples from patients who have undergone biopsies or surgical procedures,” Guerriero says.
Guerriero is director of the Breast Tumor Immunology Laboratory (B-TIL), which she has been building together with her mentor, Elizabeth Mittendorf, MD, PhD, the Rob and Karen Hale Distinguished Chair in Surgical Oncology and director of Dana-Farber’s Breast Immuno-Oncology Program.
Studying resistance to immunotherapy
The B-TIL lab obtains samples of blood, tumors, and other patient tissues for studies focused on the immune regulation of breast cancer. Making use of this precious tissue, Guerriero is working to understand why tumors may be resistant to T-cell immunotherapy, and to identify novel targets for immunotherapy. She is especially interested in the role of immune cells, and the relationship of T-cells and macrophages, cells that can suppress the immune system’s ability to fight tumors, but also can be part of an antitumor response.
Guerriero notes that women with breast and ovarian cancer may initially respond to therapy with PARP inhibitor drugs, but usually relapse because the cancer becomes resistant. There is evidence, she says, that suppressive macrophages surrounding the tumor eventually sap the power of the T cells to fight the tumor.
However, with funding from the Susan G. Komen organization, Guerriero is studying the potential of eliminating suppressive macrophages from the tumor, or even teaching those macrophages to become anti-tumor macrophages.
Using tumor samples to identify effective drugs
Sarah Hill, MD, PhD, is a women’s and perinatal pathologist by training, and an associate pathologist in the laboratory of Alan D’Andrea, MD, director of the Susan F. Smith Center. A major focus of her research is ovarian cancer, and she has been using cancer cells from surgical specimens to create “organoids” — minuscule spheres of cells that mimic a tumor. She and D’Andrea are testing the potential of ovarian organoids to rapidly screen drugs and identify those that are likely to be effective against a specific patient’s tumor.
Hill is always excited to get a call from an operating room at Brigham and Women’s Hospital when a new patient tumor sample is available. She carries a bag containing wet and dry ice and special vials to hold the specimens as she dashes several blocks from the operating room to the D’Andrea laboratory, where the cancer cells are processed and grown in laboratory culture. On weekends she does the painstaking work of dividing the tumor cells and placing them in laboratory dishes with the nutrients they need to thrive and grow.
The organoids that develop from the patients’ cells take a few days to a week to form. They are very small, but if you hold the plate up to the light, you can see the dots that are the organoids, and functional capabilities of each patient’s unique tumor can be deciphered in a matter of days to weeks.
Ovarian cancer is particularly interesting to her because some of the tumors have a defective DNA damage repair mechanism that can be exploited by drugs like PARP inhibitors and newer DNA damage agents. Hill’s work now focuses on understanding the mechanisms of specific DNA damage repair defects in ovarian cancer and how best to target them with funding from the Department of Defense Ovarian Cancer Research Program and the American Association for Cancer Research.
Hill says she knew she wanted to be involved in science and medicine from a young age, in part because of medical issues — one of which required an MRI scan of her brain when she was in third grade: she found it all fascinating. After graduating from Harvard, she spent a year at Oxford University as a Rhodes Scholar, studying yeast genetics. Returning to Boston, she earned her medical degree at Harvard Medical School and her PhD at Harvard University, in the laboratory of David Livingston, MD, chair of Dana-Farber’s Executive Committee for Research.