Some melanomas, sarcomas and renal cell carcinomas, but not all, have been found to respond dramatically to new drugs called immune checkpoint blockers, which exploit the body’s known capability to mount an immune response against the foreign antigen-bearing tumor cells. Now a new study published in the journal Nature in January 2020 shows that the presence of B cells within the tumor, inside knots of immune cells called tertiary lymphoid structures (TLS), could predict how well these tumors will respond to this immunotherapy.
Lymphocyte, Closeup view of B-cell. 3D illustration. Image Credit: Kateryna Kon / Shutterstock
Checkpoint inhibitors are among the newer and more effective weapons in the fight against cancer cells, but all tumors fail to show the same type and extent of response. It is important for researchers to be able to pick out markers that show how well the tumor is likely to regress when treated with these drugs, and thus screen patients for their chances of going into remission while on them.
The current study, which was first presented at the American Association for Cancer Research Annual Meeting in 2019, shows that enrichment of antibody-secreting B cells in the tumor is a marker of positive tumor response in patients with melanoma, sarcomas of the soft tissue and renal cell carcinomas. The B cells inside the TLS appear to be essential to block the immune checkpoints. This indicates that for antitumor immunity to operate, 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 don’t, the non-responders. An earlier study by researchers at the same institute showed that the greatest differences in gene expression between these two classes occurs in terms of B cell markers. The current findings add to this, showing that B cells drive cancer immunotherapy and in particular checkpoint inhibitors. As a result, says researcher Jennifer Wargo hopefully, “This could lead us to important biomarkers for therapy response as well as potentially new therapeutic options.”
The researchers examined samples of tumor from patients with advanced melanomas who were being treated either with neoadjuvant therapy, or with checkpoint inhibitors before surgery. Another set of patients had renal cell carcinoma with distant spread of the tumor and were on neoadjuvant therapy including checkpoint blockade within a clinical trial.
Tumor samples were taken from all the patients at the beginning of the study and repeated throughout treatment. These were tested for immune cell markers.
The findings showed that the expression of B cell-linked genes was much higher in those patients who responded well to checkpoint blockade drugs. To confirm this, samples from the network called The Cancer Genome Atlas were also checked. Here again, increased B cell marker expression predicted a much better overall survival.
This shows that other immune cells than just T cells play a very important role in the antitumor immune response. Researcher Padmanee Sharma says, “There is a great need to identify biomarkers of response to therapy, and these data may allow for future studies focused on developing composite biomarkers that represent both the T- and B-cell responses.”
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.
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.
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