Cancer's gene-determined 'immune landscape' dictates progression of prostate tumors

January 12, 2018, Beth Israel Deaconess Medical Center
Wild type human prostate cells from an organoid (a man-made construct that resembles an organ). These cells have come from a xenograft where they serve as controls for the study of primary prostate cancer tumor cells, which are also injected into mice and then extracted for characterization. Credit: National Cancer Institute, National Institutes of Health

The field of immunotherapy - the harnessing of patients' own immune systems to fend off cancer - is revolutionizing cancer treatment today. However, clinical trials often show marked improvements in only small subsets of patients, suggesting that as-yet unidentified variations among tumors result in distinct paths of disease progression and response to therapy.

Now, researchers at the Cancer Center at Beth Israel Deaconess Medical Center (BIDMC) have demonstrated that genetic variations driving determine the composition of the that have been found to infiltrate primary prostate tumors. These immune , in turn, dictate and response to treatment. The data, published in Nature Medicine, suggest that profiling patients' tumors based on this new information could lead to more successful clinical trials and tailored therapies for patients.

"We observed that specific genetic events resulted in striking differences in the composition of immune cells present in and around the tumor - results with important therapeutic implications," said senior author Pier Paolo Pandolfi, MD, PhD, Director of the Cancer Center and Cancer Research Institute at BIDMC. "Our data may be especially relevant for tailoring immunological therapies and for identifying responsive-patient population."

The third leading cause of -related death in U.S. men, prostate cancer, is linked to a number of diverse genetic mutations that drive the disease. For example, the loss of the PTEN is a frequent event in prostate cancer and is well known to promote the disease in combinations with a plethora of other mutations. Researchers also know that the tumor's microenvironment - the blood vessels, immune cells, signaling molecules and other factors that surround the tumor - plays an important role in tumor progression and response to therapy.

Pandolfi's team - including lead author, Marco Bezzi, a post-doctoral fellow in Pandolfi's lab - engineered mice models to represent four distinct known genetic variations of human prostate cancer. The models lacked either Pten alone or in combination with other genetic alterations known to drive the disease. When the team analyzed the tumors from these mice, they saw profound differences in the types and relative numbers of the immune cells that had accumulated in and around the tumor, what they call the tumors' "immune landscape".

For example, specific immune landscapes tumors from the genetic model lacking both Pten and the tumor suppressor gene called Trp53 demonstrated an increased accumulation of myeloid cells, the immune cells that mediate immunosuppression. In stark contrast, tumors from the genetic model lacking Pten and a different tumor suppressor gene called PML lacked intratumoral immune infiltration; that is, the researchers observed no immune cells at all in these tumors, which the scientists dubbed "cold," or "immune-deserts." All four mouse models analyzed presented very distinctive immune landscapes and these differences were maintained and exacerbated over time.

The research team also demonstrated that these differences in immune cell composition were directly dictated by the tumors themselves because of their genetic variations. Different tumors, they observed, secreted distinct chemical attractants, which in turn recruited - or didn't recruit, in the case of the immune-desert tumors - different immune cell types into the tumor. Pandolfi and colleagues further demonstrated that these differences hold true in human prostate cancer. Critically, the immune cells recruited to the tumors were found to be essential in supporting the growth and progression of these tumors.

"We observed that when present, these infiltrating immune cells were required for the tumor to thrive and found therapies to block their recruitment to be effective," said Bezzi. "On the other hand, the cancer genotype characterized by the so-called 'immune desert' phenotype, did not respond to such therapies. On this basis, we can predict the tumor response to immunotherapies and tailor treatment modalities to effectively impact tumors that are otherwise extremely aggressive," he said.

Thus, because immune cells interact with and also affect response to , these findings may be especially relevant for the development of more precise and effective combinations of immunotherapies and targeted therapies on the basis of the cancer genetic makeup.

"These profound differences in immunological landscapes among various cancer genotypes further highlight the need to thoroughly investigate and integrate genotypes and immune-phenotypes in the context of exploratory cancer treatments in both preclinical and clinical settings," said Pandolfi.

Explore further: Combination immunotherapy targets cancer resistance

More information: Diverse genetic-driven immune landscapes dictate tumor progression through distinct mechanisms, Nature Medicine (2018). nature.com/articles/doi:10.1038/nm.4463

Related Stories

Combination immunotherapy targets cancer resistance

November 22, 2017
Cancer immunotherapy drugs have had notable but limited success because in many cases, tumors develop resistance to treatment. But researchers at Yale and Stanford have identified an experimental antibody that overcomes this ...

The immune cells that help tumors instead of destroying them

December 12, 2017
Lung cancer is the leading cause of cancer-associated deaths. One of the most promising ways to treat it is by immunotherapy, a strategy that turns the patient's immune system against the tumor. In the past twenty years, ...

Researchers uncover novel mechanism by which tumors evade cancer immunotherapies

November 10, 2017
A Ludwig Cancer Research study led by Benoit Van den Eynde, Director of Ludwig Brussels, has identified a novel mechanism by which tumors of the aggressive skin cancer melanoma can resist cancer immunotherapy. Their paper, ...

Colorectal cancers may mutate to escape immune system detection in many ways

October 30, 2017
Whole exome sequencing revealed that colorectal cancers with high mutational load (MSI-H) predominantly use "immunoediting" to escape immune surveillance while colorectal cancers with low mutational load (MSS) use oncogenic ...

Molecular fingerprint of breast tumors linked to immune response in bloodstream

September 28, 2017
Using newly developed software, researchers have shown that genes and molecular processes in breast cancer tumor cells are tightly linked to genes and processes in blood cells, including immune system cells. The findings ...

Immune suppressor cells identified for advanced prostate cancer

December 21, 2015
Immune suppressor cells called MDSCs (myeloid-derived suppressor cells) may be important in developing treatments for advanced prostate cancer, according to a study at The University of Texas MD Anderson Cancer Center.

Recommended for you

Eating foods with low nutritional quality ratings linked to cancer risk in large European cohort

September 18, 2018
The consumption of foods with higher scores on the British Food Standards Agency nutrient profiling system (FSAm-NPS), reflecting a lower nutritional quality, is associated with an increased risk of developing cancer, according ...

CRISPR screen reveals new targets in more than half of all squamous cell carcinomas

September 18, 2018
A little p63 goes a long way in embryonic development—and flaws in p63 can result in birth defects like cleft palette, fused fingers or even missing limbs. But once this early work is done, p63 goes silent, sitting quietly ...

Could the zika virus fight the brain cancer that killed john McCain?

September 18, 2018
(HealthDay)—Preliminary research in mice suggests that the Zika virus might be turned from foe into friend—enlisted to curb deadly glioblastoma brain tumors.

Enlarged genotype-phenotype correlation for a three-base pair deletion in neurofibromatosis type 1

September 18, 2018
International collaborative research led by Ludwine Messiaen, Ph.D., shows that while a three-base pair, in-frame deletion called p.Met992del in the NF1 gene has a mild phenotype for people with the genetic disorder neurofibromatosis ...

Your teen is underestimating the health risks of vaping

September 17, 2018
Teens today are more reluctant to smoke cigarettes than their counterparts nearly three decades ago, according to a study released this summer. But parents should hold their collective sigh of relief. The study, carried out ...

Artificial intelligence can determine lung cancer type

September 17, 2018
A new computer program can analyze images of patients' lung tumors, specify cancer types, and even identify altered genes driving abnormal cell growth, a new study shows.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.