The likelihood of a patient responding to immune checkpoint blockade may depend on B cells in the tumor, located within specialized immune-cell clusters known as tertiary lymphoid structures, according to three studies all recently published in Nature. The studies showed that enrichment of B cells in tertiary lymphoid structures was predictive of response to checkpoint blockade in patients with melanoma, soft-tissue sarcoma, and renal cell carcinoma.
The current studies concluded that the presence of B cells and their location within tertiary lymphoid structures, which act as a lymph node within the tumor, is critical for response to checkpoint blockade, suggesting a dynamic interaction between several components of the immune system.
B Cells and Tertiary Lymphoid Structures
In the first study, published by Helmink et al in Nature, researchers found that B-cell markers were the most differentially expressed genes in responders relative to nonresponding patients, and B cells in the tumors of responding patients appeared to be more mature and specialized. These findings were first presented by Reddy et al at the 2019 American Association for Cancer Research Annual Meeting.
“These findings open up a whole new area—that B cells are actually big drivers in cancer immunotherapy, specifically, checkpoint blockade,” said corresponding author Jennifer Wargo, MD, Professor of Genomic Medicine and Surgical Oncology at The University of Texas MD Anderson Cancer Center. “This could lead us to important biomarkers for therapy response as well as potentially new therapeutic options.”
“These findings open up a whole new area—that B cells are actually big drivers in cancer immunotherapy, specifically, checkpoint blockade. This could lead us to important biomarkers for therapy response as well as potentially new therapeutic options.”— Jennifer Wargo, MD
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The team analyzed samples from patients with advanced melanoma receiving neoadjuvant checkpoint inhibitors. The researchers also studied a group of patients with metastatic renal cell carcinoma being treated with neoadjuvant checkpoint blockade. Tumor samples were collected from patients at baseline and during treatment through the APOLLO platform, and detailed immune profiling was completed in part by the immunotherapy platform.
In each cohort, the expression of B cell–related genes was significantly higher in responders and was predictive of response to checkpoint blockade. These findings were further corroborated in an analysis of curated melanoma samples from The Cancer Genome Atlas, in which high expression of B-cell markers was associated with significantly improved overall survival.
The researchers determined that B cells were localized in the tertiary lymphoid structures, and the density of B cells and tertiary lymphoid structures in the tumor was higher in responders. Further analysis of these infiltrating B cells showed that those in responders expressed more markers of mature and differentiated B cells, such as memory B cells and plasma cells.
“Through these studies, we find that B cells are not just innocent bystanders but are themselves contributing in a meaningful way to the antitumor immune response,” said first author Beth Helmink, MD, PhD, a surgical oncology fellow at MD Anderson.
Dr. Wargo also collaborated on another study published by Cabrita et al in Nature, which analyzed an additional group of patients with metastatic melanoma and similarly suggests an important role for B cells within these lymphoid structures.
The researchers continue work to clarify the precise role for B cells in driving responses but suggest they may be producing tumor-specific antibodies that could be leveraged for future therapeutic approaches to enhance checkpoint blockade.
B Cells and Immunotherapy Response in Patients With Sarcoma
In a cancer type previously thought to be refractory to immunotherapy, profiling of soft-tissue sarcomas established five distinct classes of the disease that predict survival outcomes and response to checkpoint blockade. Those with the best outcomes were marked by enrichment of B cells within tertiary lymphoid structures in the tumor, according to results published by Petitprez et al in Nature.
“These results suggest there may be new ways of predicting responses to immunotherapy by including B cells as a novel biomarker,” said study coauthor Hussein Tawbi, MD, PhD, Associate Professor of Melanoma Medical Oncology at MD Anderson. “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.”
“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.”— Hussein Tawbi, MD, PhD
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Researchers sought to characterize sarcomas by their immune characteristics by profiling expression of immune-related genes in more than 600 patient samples. The resulting classifications grouped sarcomas into five classes, ranging from “immune-desert” tumors to “immune-high” tumors.
Patients who had tumors with highest levels of immune markers had significantly longer overall survival when compared to those with immune-desert sarcomas. The expression of B-cell markers was the strongest factor associated with survival in these patients.
A closer look at tumor samples revealed that tertiary lymphoid structures existed almost exclusively in the immune-high tumors, and these structures had high densities of many immune cell types, including B cells.
To investigate correlations with response to checkpoint blockade, the researchers analyzed pretreatment samples from patients enrolled in SARC028, a multicenter trial performed through the Sarcoma Alliance for Research through Collaboration and led by Dr. Tawbi. Patients on this trial had metastatic soft-tissue sarcomas and were treated with programmed cell death protein 1 checkpoint blockade.
There were no responders among those with low expression of immune markers, but half of patients in the immune-high class saw a response to checkpoint blockade. These patients also had a significantly improved progression-free survival compared to those in the immune-desert classification.
“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,” said Dr. Tawbi. “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 authors are working to validate these findings in a broader cohort of patients and to identify the underlying mechanisms for B cells acting in the tumor, but they suggest these findings can be used to build a novel risk-stratification tool for better utilizing immunotherapies in patients with sarcoma.
Disclosure: For full disclosures of all study authors, visit nature.com.
