Missing surface proteins allow small cell lung cancer cells to hide from immune defenses

Small cell lung cancer cells (SCLCs) lack surface proteins that stimulate an immune response, allowing them to hide from one of the body’s main cancer defenses, a new study led by UT Southwestern researchers suggests. The findings, reported online today in Cancer research, a journal of the American Society for the Study of Cancer, could lead to new treatments for SCLC, which do not have effective treatments.

Despite decades of study, SCLC – a subset of lung cancer that makes up about 13 percent of lung cancer diagnoses – has a very poor prognosis with only about 6 percent of patients surviving five years after the judgment. For the past 30 years, this disease has been treated with a combination of chemotherapies. While most SCLC tumors respond to treatment first, most patients relapse within a year.

These tumors tend to carry many genetic mutations – they are often a good predictor of a strong immunotherapy response. However, says Esra Akbay, Ph.D., professor of pathology and member of the Harold C. Simmons Comprehensive Cancer Center at UTSW, immunotherapy drugs do not tend to work well for SCLC patients, typically extending survival. just a few months.

The inability of SCLC to respond to immunotherapy led us to think that there may have been something about these tumors that allowed evolution to hide from the immune system. We thought that there may be deficiencies in how these tumors communicate with immune cells that should be recognized as cancerous. “

Esra Akbay, Ph.D., Associate Professor of Pathology, UTSW

To explore this hypothesis, Akbay and her colleagues looked at publicly available cancer datasets from patient tumors and data collected from human tumor cell lines at UTSW to compare proteins on the surface of SCLC cells. against non-small cell lung cancer (NSCLC), which tends to respond better to immunotherapy. They quickly noticed that SCLC cells were missing the surface protein NKG2DL, which is known to interact with natural killer cells (NK). NK cells make up a key part of the immune system, an old metastatic part of the body’s natural immune system that constantly monitors foreign invaders to launch an attack.

Data from mouse models of SCLC confirmed that the rodent version of NKG2DL was also missing from the surface of their cancer cells. When the researchers examined the tumors of the animals, they found significantly fewer immune cells compared to those from mouse models of NSCLC. Moreover, the immune cells in SCLC tumors were not activated and therefore not ready for fight.

To better understand the role of NKG2DL in SCLC immunity, Akbay and her colleagues genetically manipulated SCLC cell lines to induce the production of this protein on their supernatants. When they placed these cells in mice, they grew smaller tumors and were less likely to spread. These tumors had a much higher number of immune cells than SCLC tumors that did not express NKG2DL, and many more of the immune cells in tumors with NKG2DL were activated and ready to fight.

Akbay explains that some chemotherapy drugs can stimulate the surface of NKG2DL; however, when she and her colleagues downgraded SCLC cell lines with these drugs, they did not stimulate the cells to produce this protein. Further studies showed that the gene for NKG2DL was not suppressed, suggesting that this protein was missing due to a problem with mutation of the gene, rather than a defective gene.

Certainly, further experiments have shown that, in SCLC cells, the NKG2DL-responsible gene is secreted behind DNA by a tight junction, making it impossible for the cell apparatus that translated this gene to protein access to it. When the researchers administered doses of animal models of SCLC with drugs called histone deacetylase inhibitors (HDACs), which released DNA corals, the SCLC cells began to express NKG2DL on their surfaces. , translating to much smaller tumors in which immune cells were more active.

Turning again to a public cancer data set, the researchers found that neuroblastoma – one of the most common childhood cancers – also commonly depletes NKG2DL on the surface of its cells. When the researchers administered doses of neuroblastoma cell lines with HDAC inhibitors, they also began to express the surface of NKG2DL.

Taken together, Akbay says, these findings could lead to new ways to more accurately predict patient prognosis and better manage treatment options for SCLC, neuroblastoma, and other cancers that may to be there. Patients with NKG2DL tumor cell surface that are less likely to respond to immunotherapy drugs may have a more aggressive infection, she explains. But the hope is that treatment with HDAC immunosuppressants could boost patients ’immune systems to fight these tumors, increasing the effectiveness of immunotherapy.

“The more we know about how the immune system interacts with cancer,” Akbay says, “the more we can take advantage of the body’s sexual immune system to fight the this disease. “