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The TLS was found to be the home of densely packed B cells. The number of TLS within the tumor was increased in responders, as was the B cell density. Not only so, the B cells themselves expressed markers that characterize mature differentiated B cells. Such markers are also found in long-term memory B cells and in plasma cells.
As a result, the investigators think that B cells are not simply “innocent bystanders” but are found to be relevant to the regulation of anti-tumor immunity. B cells and sarcomas
The study is echoed by another piece of research which suggests that B cells within their TLS are essential for their normal role in fighting melanoma that has spread through the body. The next challenge is to identify just what B cells do in fighting the tumor other than producing specific antibodies. This knowledge could be exploited in later checkpoint blockade therapies.
Soft tissue sarcomas generally show little or no response to immunotherapy. There are more than 50 subtypes of soft tissue sarcomas, but their microscopic appearance doesn’t help much to predict their biological behavior. Instead, Tawbi and the team characterized the immune gene profile, taking data from over 600 patient tumor samples.
By analysing and classifying these patterns, Tawbi was able to come up with 5 tumor classes that actually predict how the tumor will respond. The five classes range from “immune desert” tumors to “immune high” tumors. The best outcomes occurred in those tumors with enriched B cells within the TLS.
The higher the immune marker expression, the longer was the overall patient survival. B cell marker expression was the strongest marker of better survival. TLS were present almost only in those tumors which were “immune high”, and contained an abundance of multiple immune cell types, including B cells. Predicting immunotherapy response, enhancing B cell function
This study was also published simultaneously with the preceding one reported above. Says researcher Hussein Tawbi, “These results suggest there may be new ways of predicting responses to immunotherapy by including B cells as a novel biomarker. Perhaps most exciting is this also opens up the possibility for a therapeutic targeting of B cells in ways that could identify new avenues for treating these patients."
The researchers also examined tumor samples from soft tissue sarcoma patients taking part in the multicentre SARC028 trial. These samples were taken before the start of treatment. Here again, tumors with a low level of expression of immune markers showed poor response to immune checkpoint blockage, but there was a 50% response among the “immune high” tumor class. Moreover, the latter also had a significantly longer progression-free survival compared to patients with “immune desert” class tumors. Implications
Tawbi sums up: “All of the patients that responded to checkpoint inhibitors did truly have those immune-high signatures, especially with enriched B cells, highlighting the fact that there might be a really important role for these cells in the response to immunotherapy. Based on these results, it may now be possible for us to identify more types of sarcomas for which we can use immunotherapy effectively.”
The researchers are going ahead to establish their findings in a larger group of patients. They also would like to find out how B cells are operating to enhance antitumor immunity. They feel these findings could be important in setting up an approach to tumor classification which would help to identify those patients with sarcoma that will probably respond best to immunotherapy. Journal reference:
Helmink, B.A., Reddy, S.M., Gao, J. et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature (2020) doi:10.1038/s41586-019-1922-8, https://www.nature.com/articles/s41586-019-1922-8
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