Medical Bulletin 02/ March/ 2024

In a recent study by MIT and Dana-Farber Cancer Institute, researchers uncovered a mechanism employed by precancerous cells to evade immune surveillance. Activation of the gene SOX17 during early colon cancer stages makes these cells nearly undetectable by the immune system.

SOX17, active in embryonic development, influences intestinal and blood vessel development. Inhibiting SOX17 or its pathway may offer a new strategy to treat early-stage colon cancer before it progresses. Over time these large tumor cells can accumulate mutations, forming polyps that may evolve into metastatic colon cancer.

“Activation of the SOX17 program in the earliest innings of colorectal cancer formation is a critical step that shields precancerous cells from the immune system. If we can inhibit the SOX17 program, we might be better able to prevent colon cancer, particularly in patients that are prone to developing colon polyps,” says Omer Yilmaz, an MIT associate professor of biology, a member of MIT’s Koch Institute for Integrative Cancer Research, and one of the senior authors of the study.

To understand how precancerous growths avoid immune detection, researchers employed a method to cultivate mini colon tumours in a laboratory dish, subsequently implanting them into mice. These tumours were engineered to carry mutated forms of the cancer-associated genes Kras, p53, and APC, commonly found in human colon cancers. Upon implantation in mice, researchers noted a significant upregulation of SOX17 expression within the tumours.

The findings revealed that when SOX17 is activated in cancer cells, it fosters an immunosuppressive environment by inhibiting the synthesis of interferon-gamma receptors, crucial for the immune response against cancer. This prevents cells from neglecting signals for programmed cell death, evading immune attack.

“One of SOX17’s main roles is to turn off the interferon-gamma signalling pathway in colorectal cancer cells and in precancerous adenoma cells. By turning off interferon-gamma receptor signalling in the tumour cells, the tumour cells become hidden from T cells and can grow in the presence of an immune system,” Yilmaz says.

In the absence of interferon-gamma signalling, cancer cells reduce MHC protein production, impeding the display of cancerous antigens to the immune system, and hinder the production of chemokines, which recruit T cells to eliminate the cancerous cells.

Reference: Pelka, K. et al. Spatially organized multicellular immune hubs in human colorectal cancer. Cell DOI: 10.1038/s41586-024-07135-3

Immunotherapy combinations may aid patients with advanced skin cancers following kidney transplants

People who have had a kidney transplant are at high risk for developing skin cancers. Now, Researchers from the Johns Hopkins Kimmel Cancer Center have discovered the optimal treatment combination to address skin cancers while safeguarding transplanted organs.

The study, published in the Journal of Clinical Oncology, revealed a novel drug combination aimed at boosting the immune system to combat advanced, potentially life-threatening skin cancers without causing permanent harm to patients' transplanted kidneys. The regimen involved two immune-suppressing drugs to safeguard the transplanted kidney, along with either one or two checkpoint inhibitors, which activate the immune system to target cancer cells.

“Organ transplant recipients develop skin cancers at an exponentially higher rate compared with the general population because they receive long-term immunosuppressive drugs to prevent rejection of the transplanted organ. This can stop the immune system from recognizing and attacking cancers as they form” says Evan Lipson, M.D., an associate professor of oncology at the Johns Hopkins University School of Medicine and Kimmel Cancer Center.

In the Experimental Therapeutics Clinical Trials Network trial, eight kidney transplant recipients with advanced skin cancers received low-dose tacrolimus and prednisone, followed by nivolumab. Upon progression, ipilimumab was added to treatment in six patients. Donor-derived cell-free DNA levels were also monitored every two weeks to explore their potential as a predictor of graft rejection.

Researchers observed that the tumour biopsies demonstrated increased immune activity against cancer with nivolumab, and a complete response in two patients after ipilimumab addition. Additionally, donor-derived cell-free DNA levels rose before serum creatinine increased, indicating a potential for predicting kidney damage from trial medications.

“The completed study introduced two checkpoint inhibitors sequentially because we didn’t want to risk overstimulating the patient’s immune system and harm the transplanted organ,” Lipson said. “But some cutaneous tumors grow so quickly we can’t wait to give a second immunotherapy drug months after starting a first.”

“Going forward, this knowledge may help us intervene earlier and better preserve the transplanted organ, a precious resource,” concluded Lipson.

Reference: DC Dapprich, RH Weenig, AL Rohlinger, etal: Outcomes of melanoma in recipients of solid organ transplant J Am Acad Dermatol 59: 405– 417,2008; https://doi.org/10.1200/JCO.2013.49.2314

Neurons assist in the removal of waste from brain during sleep

Scientists at Washington University School of Medicine in St. Louis have found that brain waves help flush waste out of the waste during sleep. Individual nerve cells coordinate to produce rhythmic waves that propel fluid through dense brain tissue, washing the tissue in the process.

During sleep, when the body is at rest, the brain cells produce bursts of electrical pulses that cumulate into rhythmic waves -- a sign of heightened brain cell function. Cerebrospinal fluid surrounding the brain enters and weaves through intricate cellular webs, collecting toxic waste as it travels. Upon exiting the brain, the contaminated fluid must pass through a barrier before spilling into the lymphatic vessels in the dura mater -- the outer tissue layer enveloping the brain underneath the skull.

"The neurons are miniature pumps. Synchronized neural activity powers fluid flow and removal of debris from the brain," explained first author Li-Feng Jiang-Xie, PhD, a postdoctoral research associate in the Department of Pathology & Immunology. "If we can build on this process, there is the possibility of delaying or even preventing neurological diseases, including Alzheimer's and Parkinson's disease, in which excess waste -- such as metabolic waste and junk proteins -- accumulate in the brain and lead to neurodegeneration."

Researchers studied the brain of sleeping mice and discovered that neurons generate rhythmic brain waves, driving cleaning processes by facilitating fluid movement. Silencing specific brain regions halted these waves, preventing fresh cerebrospinal fluid flow and trapping waste in brain tissue.

"One of the reasons that we sleep is to cleanse the brain," said Jonathan Kipnis, Professor of Pathology & Immunology and a BJC Investigator. "And if we can enhance this cleansing process, perhaps it's possible to sleep less and remain healthy. Not everyone has the benefit of eight hours of sleep each night, and loss of sleep has an impact on health. Other studies have shown that mice that are genetically wired to sleep less have healthy brains.”

Brain wave patterns change throughout sleep cycles. Taller brain waves with larger amplitude move fluid with more force. The research could help people living with insomnia by enhancing their brain's cleaning abilities so they can function well on less sleep.

Reference: Li-Feng Jiang-Xie, Antoine Drieu, Kesshni Bhasiin, Daniel Quintero, Igor Smirnov, Jonathan Kipnis. Neuronal dynamics direct cerebrospinal fluid perfusion and brain clearance. Nature, 2024; DOI: 10.1038/s41586-024-07108-6