It has been found that some melanomas, sarcomas and renal cell carcinomas, but not all, respond drastically to new medications called immune control point blockers, which exploit the body’s known ability to mount an immune response against tumor cells with strange antigens. Now a new study published in the magazine Nature In January 2020, it shows that the presence of B cells within the tumor, within nodes of immune cells called tertiary lymphoid structures (TLS), could predict how well these tumors will respond to this immunotherapy.
Lymphocyte, Close-up view of B cells. 3D illustration Image credit: Kateryna Kon / Shutterstock
Control point inhibitors are among the newest and most effective weapons in the fight against cancer cells, but all tumors do not show the same type and degree of response. It is important that researchers can select markers that show how well the tumor is likely to recede when treated with these medications and, therefore, evaluate patients to see if they are likely to go into remission while they are being treated.
The current study, which was first presented at the Annual Meeting of the American Association for Cancer Research in 2019, shows that enrichment of tumor-secreting B cells in the tumor is a marker of positive tumor response in patients with melanoma, soft tissue sarcomas and renal cell carcinomas. B cells within the TLS appear to be essential for blocking immune control points. This indicates that for antitumor immunity to function, multiple parts of the immune system need to operate in a dynamic and interrelated pattern.
Responders and mature B cells
Patients with these tumors can be divided into those who respond satisfactorily to tumor immunotherapy, called responders, and those who do not respond, those who do not respond. An earlier study by researchers from the same institute showed that the greatest differences in gene expression between these two classes occur in terms of B cell markers. Current findings add to this, showing that B cells boost cancer immunotherapy. and, in particular, control point inhibitors. As a result, says researcher Jennifer Wargo with hope, “This could lead us to important biomarkers for the response to treatment, as well as to potentially new therapeutic options.”
The researchers examined tumor samples from patients with advanced melanomas who were being treated with neoadjuvant therapy or with checkpoint inhibitors before surgery. Another group of patients had renal cell carcinoma with distant dissemination of the tumor and were in neoadjuvant therapy, including control point blockage within a clinical trial.
Tumor samples were taken from all patients at the beginning of the study and repeated throughout the treatment. These were tested for immune cell markers.
The findings showed that the expression of genes linked to B cells was much higher in those patients who responded well to control point blocking drugs. To confirm this, samples from the network called The Cancer Genome Atlas were also verified. Again, the increased expression of the B cell marker predicted a much better overall survival.
This shows that other immune cells besides T cells play a very important role in the antitumor immune response. The researcher Padmanee Sharma says: “There is a great need to identify biomarkers of response to therapy, and these data may allow future studies focused on the development of compound biomarkers that represent the responses of T and B cells.”
It was discovered that TLS was home to densely packed B cells. The number of TLS within the tumor increased in responders, as did the density of B cells. 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, researchers think that B cells are not simply “innocent bystanders” but are relevant to the regulation of antitumor immunity.
B cells and sarcomas
The study echoed other research that suggests that B cells within your TLS are essential for their normal role in the fight against melanoma that has spread throughout the body. The next challenge is to identify what B cells do to fight the tumor, in addition to producing specific antibodies. This knowledge could be exploited in subsequent control point blocking 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 does not help much to predict their biological behavior. Instead, Tawbi and the team characterized the profile of the immune gene, taking data from more than 600 samples of patient tumors.
By analyzing and classifying these patterns, Tawbi was able to find 5 kinds of tumors that really predict how the tumor will respond. The five classes range from “desert immune” tumors to “high immune” tumors. The best results occurred in those tumors with enriched B cells within the TLS.
The higher the expression of the immune marker, the greater the overall survival of the patient. B cell marker expression was the strongest marker of best survival. TLS was present almost only in those tumors that were “high immune”, and contained an abundance of multiple types of immune cells, including B cells.
Predict the immunotherapy response, improve the function of B cells
This study was also published simultaneously with the previous one that was previously reported. The researcher Hussein Tawbi says: “These results suggest that there may be new ways to predict responses to immunotherapy by including B cells as a new biomarker. Perhaps the most exciting thing is that this also opens up the possibility of a therapeutic targeting of B cells so that I can identify new ways to treat these patients. “
The researchers also examined tumor samples from patients with soft tissue sarcoma who participated in the multi-center SARC028 trial. These samples were taken before the start of treatment. Here again, tumors with a low level of immune marker expression showed a poor response to the blockage of the immune control point, but there was a 50% response among the class of “high immune” tumors. In addition, the latter also had a significantly longer progression-free survival compared to patients with “desert immune” class tumors.
Tawbi summarizes: “All patients who responded to control point inhibitors actually had those immuno-high signatures, especially with enriched B cells, highlighting the fact that there could be a really important role for these cells in the response to immunotherapy. . Based on these results, it is now possible that we can identify more types of sarcomas for which we can use immunotherapy effectively. “
Researchers continue to establish their findings in a larger group of patients. They would also like to know how B cells work to improve antitumor immunity. They believe that these findings could be important in establishing an approach to tumor classification that would help identify those patients with sarcoma who are likely to respond better to immunotherapy.
Helmink, B.A., Reddy, S.M., Gao, J. et al. B cells and tertiary lymphoid structures promote the immunotherapy response. Nature (2020) doi: 10.1038 / s41586-019-1922-8, https://www.nature.com/articles/s41586-019-1922-8