1. DiGiulio, Sarah

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Small cell lung cancers (SCLC) remain a tricky type of cancer to treat. They're less common than non-small cell lung cancers, but they grow quickly and often recur after initial treatment. Despite having several mutations that would typically indicate various immunotherapies should be effective at attacking these tumors, such drugs tend to have limited and short efficacy for patients.

SCLC. SCLC... - Click to enlarge in new windowSCLC. SCLC

Now new evidence from a group of UT Southwestern Cancer Center (UTSW) researchers may help explain what's going on in these cancers. A new study revealed that a key surface protein, NKG2DL (natural killer group 2, member D ligand), that typically triggers an immune response is missing in most SCLC tumors (Cancer Res 2021; doi: 10.1158/0008-5472.CAN-20-2808).


The poor response of SCLC to immunotherapies led the researchers to suspect that somehow the cancer cells do not get seen or recognized by the immune system, explained study co-author Esra Akbay, PhD, Assistant Professor of Pathology and a member of the Harold C. Simmons Comprehensive Cancer Center at UTSW. "These proteins are known to be important in other cancers-and part of how the innate immune system recognizes tumor cells."


Better understanding why this protein doesn't show up in SCLC and how to make it show up could lead to treatment approaches in SCLC that get the body's immune response involved in attacking the cancer and take advantage of the body's inherent defense against the disease-innate immunity, Akbay explained.


Missing NKG2DL Protein

Akbay's team looked at publicly available cancer datasets of patient tumors and UTSW tumor cell lines to compare the proteins found on the surface of SCLC cells with those on the surface of non-small cell lung cancer cells. The protein that was identified as missing on SCLC cells, NKG2DL, is known to interact with natural killer (NK) cells, which are known to play an important role in the body's defense against foreign cells.


Furthermore, in mouse models of the tumors, when Akbay's team genetically modified the SCLC cells of those tumors to force them to produce NKG2DL, the resulting tumors grew slower and spread less than tumor cells that had not been genetically modified. (The results of that experiment add further evidence that NKG2DL may indeed play an important role in the body's immune response to this tumor-or lack thereof, Akbay noted.)


Finally, the researchers found that the gene responsible for making NKG2DL is found in the coiled DNA strands in the tumor cells. They suspect it was because those DNA strands were so tightly coiled that NKG2DL could not be expressed. When they dosed animal models of SCLC cells with histone deacetylase (HDAC) inhibitors-drugs known to be able to help loosen DNA coils within cells-the NKG2DL protein began to show up on the SCLC cells.


HDAC Inhibitors + Immunotherapy

Akbay noted that the research suggests possibly adding HDAC inhibitors to immunotherapy regimens could boost efficacy of those immunotherapies-or potentially adding them to chemotherapy regimens, too. The next step of the research is testing the hypothesis in tumor samples and eventually in clinical trials.


There also appears to be some SCLCs that do express the NKG2DL protein on their surfaces. "It's a small subset of small cell lung cancers that are actually not behaving like classical small cell lung cancer," Akbay stated. So it will be important to identify before these various treatment regimens are tried if the SCLC belong to this small subset or do not express the NKG2DL protein.


Personalizing Treatment for SCLC

This pre-clinical work is important because it suggests that lack of expression of NKG2DL may be a mechanism for SCLC's escape from NK immune surveillance, noted Nagla Abdel Karim, MD, Professor of Medicine and Medical Director of the Georgia Cancer Center Clinical Trials Program at Augusta University. Also significant from this work is that the researchers found that other neuroendocrine tumors, specifically neuroblastomas, also fail to express NKG2DL.


Because it's known that not all SCLC patients respond equally to immunotherapy, it may be that tumor biopsy to better characterize tumor type and better identify treatment options to treat the various cancer subtypes will be needed in SCLC management.


"We need to explore small cell lung cancer subtypes," Karim said. "In summary, we need a personalized approach to therapy for small cell lung cancer patients." This new research may help define that approach.


Sarah DiGiulio is a contributing writer.


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