Scientists Find Biomarker Predicting Tumor Response to Immunotherapy

It has been established that some subtypes of melanoma, sarcoma, and renal cell carcinoma – but not all – respond well to treatment with new drugs known as immune checkpoint inhibitors, which utilize the body's well-known ability to generate an immune response against tumor cells carrying foreign antigens. A new study published in the journal Nature shows that the presence of B-lymphocytes within tumor clusters of immune cells called tertiary lymphoid structures (TLS) can predict how well these tumors will respond to immunotherapy.

Immune checkpoint inhibitors are among the newest and most effective means of combating cancer cells, but different malignancies demonstrate varying types and degrees of response to such treatment. It is important for researchers to identify markers that indicate how quickly a tumor shrinks under the influence of these drugs, thus helping to determine patients' chances of achieving remission after their administration.

The current study, which was first presented at the annual meeting of the American Association for Cancer Research in 2019, shows that increased levels of B-cells, or B-lymphocytes secreting antibodies, in tumor tissue are a marker of positive response to treatment in patients with melanoma, soft tissue sarcomas, and renal cell carcinomas. Presumably, the presence of B-cells within TLS is a crucial condition for blocking immune checkpoints. This suggests that for effective anti-tumor immunity, many parts of the immune system must work together in a coordinated and dynamic manner.

Responders and Mature B-Cells

Patients with the aforementioned types of tumors can be divided into those who respond to immunotherapy – referred to as responders – and those who do not respond. An earlier study conducted by scientists from the same institute showed that the greatest differences in gene expression between these two patient groups occur in terms of B-cell markers. The current study confirms this data, demonstrating that B-lymphocytes govern cancer immunotherapy and, in particular, the action of immune checkpoint inhibitors. "We hope that as a result, we will obtain important biomarkers that will predict response to therapy and may also serve as a basis for new treatment methods," says researcher Jennifer Vargo.

The team studied tumor samples from patients with progressive melanoma who underwent either neoadjuvant therapy or treatment with checkpoint inhibitors before surgical removal. Another group of patients – with renal cell carcinomas that had spread to distant organs – received neoadjuvant therapy, including immune checkpoint blockade, as part of a clinical trial. Tumor samples from all patients were collected at the beginning of the study and then throughout the treatment period. Specialists examined them for immune cell markers.

Results

The results showed that gene expression related to B-cells was significantly higher in those patients who responded well to immune checkpoint inhibitors. To confirm these findings, researchers also examined tumor samples taken from the Cancer Genome Atlas project, which aims to systematize data on genetic mutations leading to cancer development. In this case, increased expression of the B-cell marker predicted much better survival.

This indicates that not only T-lymphocytes but also other immune cells play a crucial role in forming the anti-tumor immune response. "There is a great need for response biomarkers, and the data obtained can be used in future studies to develop a set of biomarkers that will indicate responses from both T- and B-cells," says one of the researchers, Padmani Sharma.

Tertiary lymphoid structures, as researchers found, are home to densely packed B-lymphocytes. In patients who respond well to treatment, the number of TLS within tumors was increased, as was the density of B-cells. Moreover, the B-cells themselves expressed markers indicating their maturity. Similar markers were found in B-lymphocytes with long-term immunological memory and plasma cells. This led researchers to believe that B-cells are not merely "silent observers"; they appear to participate in regulating anti-tumor immunity.

B-Lymphocytes and Sarcoma

The results of the current study resonate with findings from another study, which indicated that the presence of B-cells in TLS is a necessary condition for their fight against melanoma that has spread throughout the body. Now researchers face the task of determining how exactly B-lymphocytes help combat cancer, aside from producing specific antibodies. This knowledge could be used in developing new methods for blocking immune checkpoints.

Soft tissue sarcomas typically show either a weak response to immunotherapy or a complete lack of response. There are over fifty subtypes of sarcomas, but their microscopic appearance does not particularly help in predicting their behavior. Instead, researchers identified the genetic profile of the immune response based on data from more than 600 tumor samples.

By analyzing and classifying the identified characteristics, the team was able to define five classes of tumors, the affiliation to which allows predicting how a particular tumor will respond to treatment. The best results were predictably obtained for those neoplasms whose TLS were rich in B-cells.

The higher the expression of the immune marker, the higher the overall survival rate. The expression of the B-cell marker turned out to be the strongest marker of better survival. Tertiary lymphoid structures were primarily present only in those tumors that contained many different types of immune cells, including B-lymphocytes.

Predicting Response to Immunotherapy

"The results obtained indicate the potential emergence of new ways to predict tumor response to immunotherapy, using B-cells as a new biomarker," says researcher Hussein Taubi. "This also opens up possibilities for therapeutic interventions on B-lymphocytes and the development of new treatment methods for these patients."

Researchers also examined tumor samples from patients with soft tissue sarcomas participating in the multicenter SARC028 study. These samples were taken before the start of treatment. Again, it turned out that tumors with low expression of immune markers demonstrated a weak response to checkpoint inhibitor therapy, and vice versa. Moreover, among patients with increased expression of immune markers, longer progression-free survival was recorded.

Conclusions

"All patients who responded well to treatment with immune checkpoint inhibitors indeed exhibited pronounced immune characteristics, particularly high concentrations of B-cells, highlighting the fact that these cells may play a truly important role in the body's response to immunotherapy," notes Dr. Taubi. "Based on these results, we will be able to identify more types of sarcomas for which immunotherapy can be successfully employed."

Researchers intend to confirm their findings in a larger group of patients. They also plan to determine how exactly B-lymphocytes enhance anti-tumor immunity. All this knowledge could be used in developing an approach to tumor classification that would help identify patients with sarcoma who are most likely to respond best to immunotherapy.