Bone metastases are devastating developments of cancers that originate in other organs. In the case of metastatic prostate cancer, bone metastases represent an incurable, painful, and often deadly development, killing more than 30,000 American men every year. Unlike many other tumor types, metastatic prostate cancer responds poorly to immune-based therapies, but a new study published in Cancer Cell and originating in part from Harvard Stem Cell Institute (HSCI) labs, has uncovered a key mechanism for why such therapies fail to work, potentially leading the way to a breakthrough in the treatment of this devastating disease.
This study began in 2015, when a multi-disciplinary team of doctors, surgeons, researchers, and bioinformaticians from HSCI, Massachusetts General Hospital (MGH), and Harvard Medical School (HMS) assembled to address the question: “Why does prostate cancer so commonly spread to the bone and why can’t we treat it with immune therapy?” The team focused on bone marrow, where the immune system is generated and where prostate cancer establishes its metastases.
“Given that all blood and most immune cells are being made in the bone marrow, it has been unclear why metastases to bone respond so poorly to immune therapies,” said
Using samples from patients whose prostate cancer had spread to the bone marrow of their spines, the team looked for how metastatic tumor evaded these usually effective therapies. The tumor, they found, were able to bias the differentiation of normal hematopoietic stem cells towards an abnormal inflammatory myeloid population.
“We found that a group of immune cells, called myeloid cells, have distinctive features when metastatic cancer cells are present,” explained Scadden, a professor in the Harvard Department of Stem Cell and Regenerative Biology. “They send a signal that turns off the immune attack of T cells.”
Specifically, the bias created by the tumor led to generation of myeloid-derived suppressor cells (MDSC), which are capable of inhibiting the normal T-cell response against the tumor within the bone marrow. Because immune therapies rely on this defensive T-cell response, these abnormal cells effectively rendered such treatments useless.
The team then looked at how to counter this response. Generating a mouse model of disease, they demonstrated that by blocking the interaction between the MDSC and T-cells the dysfunctional relationship between them could be broken, “re-awakening” the T-cell immune response against the tumor and improving animal survival. This work identified specific molecules, CCL20 and its receptor CCR6, as key regulators of the immune-suppressing effect that can be targeted to improve immune targeting of prostate cancer metastases in bone. The study points to a possible new approach for patients with metastatic prostate cancer.
“We showed that interrupting that signal releases the brake and the immune system can go after tumor cells enough to extend the lifespan of animals,” said Scadden. “There are agents that have been tested in humans in other settings which target the ‘off’ signal. This work supports testing them in metastatic prostate cancer.”