Cerebrospinal Fluid Analysis to Predict Immunotherapy Response

Analysis of immune system cells infiltrating cerebrospinal fluid can characterize, in brain metastases, the tumor microenvironment, as demonstrated by a published study.

According to the study, characterizing this microenvironment in patients with brain metastases is a new method for predicting the response to immunotherapy in these patients.

An anatomical explanation of "cerebrospinal fluid" can be seen below:

- Related topic: Brain Tumor Symptoms, Stages, and Treatment

Examining Cerebrospinal Fluid for Immunotherapy Efficacy

Anti-PD1, anti-PD-L1 and anti-CTLA4 are among the immune checkpoint inhibitors (immune checkpoint inhibitors = ICIs) that have shown substantial benefits in patients with progressive (advancing) or metastatic solid (organ) tumors, including some brain metastases. In particular, these immune-based treatments have provided better outcomes for some patients with lung cancer and melanoma. These tumor types (representing 30-40% of all cancers), together with breast cancer, are the three most common cancer types that lead to brain metastases.

Nature Communications published the study, in which Joan Seoane says: “One of the major challenges in improving outcomes for patients with brain metastases caused by these cancers is that the new metastases can be extremely different from the primary (main) tumor and thus respond to immune-based therapies in a different way.”

Brain metastases are the most common brain tumors and are associated with a difficult disease course. While some patients benefit from treatment with immunotherapies, most do not. Predicting response to these treatments requires characterization of tumor samples. Obtaining samples from brain metastases is difficult because of the anatomical location of brain tumors and the risks of a surgical procedure.

The findings of a previous study led by Joan Seona, as well as those of other groups, demonstrated that cerebrospinal fluid could provide vital findings about the genomic characteristics of brain tumors and could therefore be used as a fluid / liquid biopsy.

Building on these findings, the researchers conducted this study to determine whether the immunological status of cancer cells could be effectively characterized by analyzing cerebrospinal fluid.

Study Details

To test this hypothesis, Joan Seoane's team analyzed cerebrospinal fluid (CSF) samples from 48 patients with brain metastases. These samples were obtained thanks to patients treated at Hospital Clínic in Barcelona who gave full consent for their samples to be used, as well as the generosity of patients treated at Vall d’Hebron University Hospital (HUVH). Collecting the samples was made possible by the efforts and expertise of the Neurosurgery Services at these hospitals.

The researchers assessed the presence of immune cells in brain metastases and, in parallel, profiled immune cells in cerebrospinal fluid.

They examined cerebrospinal fluid to identify which cell types were present and compared them with those obtained from the metastatic lesion.

Joan Seoane: “By establishing similarities between the two, we are identifying a new and minimally invasive method that will enable us to predict the response to immunotherapy in these patients. This pioneering approach could guide clinical decisions more precisely in treating these patients with immune-based treatment strategies.”

- Related topic: Immunotherapy and Cancer Vaccines

By analyzing cerebrospinal fluid, Joan Seoane's team was able to identify tumor-recognizing  T cells of the immune system and those that were active during treatment.

Joan Seoane: “Each T cell has a unique sequence that recognizes a specific cancer cell. When they begin tracking and targeting it, these cells become activated and start multiplying. Through this study, we were able to identify the individual sequences of immune cells, thereby identifying the immune cells fighting the tumor and distinguishing how they evolved over time.”

The study was also conducted in collaboration with the National Center for Genomic Analysis – Center for Genomic Regulation (CNAG – CRG) in Barcelona. The team led by CNAG – CRG's Head of the Single-Cell Genomics Team, Holger Heyn, sequenced the transcriptomes (the collection of all mRNAs in a particular cell) of up to 6000 cells using scRNA-seq technology.

Holger Heyn concludes the study as follows: “Single-cell transcriptome sequencing provides the highest resolution for monitoring and detecting several different diseases. Identifying clonal T cells in both metastases and liquid biopsy is particularly interesting. Importantly, this approach opens up new ways to detect systematic diseases.”

Conclusion

The study's findings show that immune cells reaching cerebrospinal fluid replicate the characteristics of the cells identified in brain metastases and may therefore serve as new biomarkers for response to immune-based therapy.