Genetic ‘Immune Landscape’ Determines Progression of Prostate Cancer, Mice Study Suggests

Genetic ‘Immune Landscape’ Determines Progression of Prostate Cancer, Mice Study Suggests

Genetic variations that drive prostate cancer dictate the composition of immune cells within tumors and response to treatment, a new study shows.

Researchers at the Beth Israel Deaconess Medical Center (BIDMC) suggest that profiling a patient’s tumor could help tailoring immunotherapies and identify patients who are most responsive to certain treatments.

The research, “Diverse genetic-driven immune landscapes dictate tumor progression through distinct mechanisms,” was published in the journal Nature Medicine.

Diverse genetic mutations can cause prostate cancer, the most common cancer in American men other than skin cancer. One example is the tumor suppressor gene Pten, whose complete loss is linked to metastasis and disease progression in prostate cancer.

In addition to gene mutations, the tumor microenvironment (the non-cancerous cells present in the tumor, including immune cells and cells comprising blood vessels), is also an important factor in disease progression and response to treatment.

The investigators created mouse models of four known genetic alterations of human prostate cancer, including deletion of Pten alone, or in combination with tumor suppressor genes Trp53Zbtb7a, or Pml.

Results showed striking differences in the types and numbers of immune cells present in the tumor’s microenvironment, also called the tumor’s “immune landscape”. These differences increased over time.

“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,” Pier Paolo Pandolfi, MD, PhD, the study’s senior author, said in a press release. Pandolfi also is director of the Cancer Center and Cancer Research Institute at BIDMC.

Specifically, whereas the mouse model lacking both Pten and Trp53 showed accumulation of myeloid cells (critical cells in the immune response), mice lacking Pten and Pml showed complete absence of immune cells in their tumors, which the researchers called “immune-deserts”.

The team found that the genetic variations in tumors determined the distinct immune cell composition. Different tumors released different chemical attractants (molecules which recruit immune cells), leading to a distinct immune cell population – or no immune cells at all in immune-desert tumors. Importantly, the results also demonstrated that these differences are present in human prostate cancer.

“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 Marco Bezzi, the study’s lead author. Bezzi added that these therapies were not effective in mice with the immune-desert tumors. “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.

As immune cells are critical factors in the tumor’s response to therapy, Pandolfi’s team results may provide an essential framework to design successful clinical trials accounting for the genetic variations in subpopulations of patients. These potentially could lead to effective immunotherapies based on each patient’s unique genetic makeup.

Collectively, the study “provides experimental evidence supporting the notion that cancer genetics plays a direct and critical role in shaping the cancer immunophenotype and the outcome of combinatorial immunotherapy,” the researchers wrote.