The benefits of B cells

HOUSTON—According to researchers at The University of Texas MD Anderson Cancer Center, 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 (TLS). Recent studies published in Nature have concluded that enrichment of B cells in TLS was predictive of response to checkpoint blockade in patients with melanoma, renal cell carcinomas (RCC) and soft-tissue sarcomas.

The studies conclude that the presence of B cells and their location within TLS, which act as a lymph node within the tumor, is critical for response to checkpoint blockade. This suggests a dynamic interaction between several immune system components.

One MD Anderson-led study found that B-cell markers were the most differentially expressed genes in responders relative to non-responders, and B cells in the tumors of responders appeared to be more mature and specialized.

“Although the distinct mechanisms through which B cells contribute are incompletely understood, our data suggest that the same properties of memory B cells and plasma cells desirable for acquired immune responses may also be contributing to an effective T cell response after ICB [immune checkpoint blockade],” the article explains. “Importantly, these B cells are probably acting together with other key immune constituents of the TLS by altering T cell activation and function as well as through other mechanisms. Memory B cells may be acting as antigen-presenting cells, driving the expansion of both memory and naive tumour-associated T cell responses.”

“These findings open up a whole new area―that B cells are actually big drivers in cancer immunotherapy, specifically checkpoint blockade,” said corresponding author Dr. Jennifer Wargo, a professor of genomic medicine and surgical oncology. “This could lead us to important biomarkers for therapy response as well as potentially new therapeutic options.”

The team analyzed samples from patients with advanced melanoma receiving neoadjuvant checkpoint inhibitors as part of a clinical trial sponsored by MD Anderson’s Melanoma Moon Shot. The researchers also studied a group of patients with metastatic RCC being treated with neoadjuvant checkpoint blockade as part of a clinical trial led by Dr. Padmanee Sharma, a professor of genitourinary medical oncology and immunology, and Dr. Jianjun Gao, an associate professor of genitourinary medical oncology.

In each cohort, the expression of B cell-related genes was significantly higher in responders and predictive of response to checkpoint blockade. 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, corroborated the findings.

“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,” explained Sharma.

Researchers determined that B cells were localized in TLS, and the density of B cells and TLS in the tumor was higher in responders. Analysis of these infiltrating B cells showed that those in responders expressed more markers of mature and differentiated B cells, like 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,” pointed out first author Dr. Beth Helmink, a fellow in surgical oncology.

Wargo also collaborated on another study led by Dr. Göran Jönsson and researchers at Lund University in Sweden. That study analyzed a group of patients with metastatic melanoma, and also suggests an important role for B cells within TLS. The researchers report that the B cells may be producing tumor-specific antibodies that could be used to enhance checkpoint blockade.

According to the authors, “In this cohort of patients treated with anti-CTLA4, the TLS signature is independent of mutational load. Moreover, the TLS signature was significantly associated with overall survival in a previously published dataset of pretreatment samples from 69 patients who were undergoing anti-PD1 monotherapy or anti- CTLA4 and anti-PD1 combination therapy … we performed meta Cox regression analysis across the four cohorts treated with ICB, using multiple immune signatures: of these, our TLS signature performed best. The TLS signature was also independent of tumour mutational load in the cohort treated with anti-PD1, consistent with previous studies that have shown that immune gene signatures are not correlated with mutational load.”

As for soft tissue sarcomas (STS), they were previously thought to be refractory to immunotherapy, but profiling of STS established five distinct classes of the disease that predict survival outcomes and responses to checkpoint blockade. Those with the best outcomes were marked by enrichment of B cells within TLS in the tumor, according to results published in January.

The study was led by Dr. Wolf Fridman and a team from Inserm, together with Dr. Hussein Tawbi, an associate professor of melanoma medical oncology at MD Anderson.

“These results suggest there may be new ways of predicting responses to immunotherapy by including B cells as a novel biomarker,” noted Tawbi. “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 profiled expression of immune-related genes in more than 600 sarcoma samples. The resulting classifications grouped sarcomas into five classes, ranging from “immune desert” to “immune high” tumors.

“Here, we found the CD8+ T cell signature and PD1 were expressed in class D and E [immune-high] SICs [sarcoma immune classes], which are associated with favorable outcomes, providing high infiltration of B cells. The integrative analysis demonstrates that infiltration by B cells is a key discriminative feature of a group of patients with improved survival. This B-cell-high group was found to respond better to PD1 blockade therapy, although this should be validated on a larger cohort,” the study states.

“Based on these results, it may now be possible for us to identify more types of sarcomas for which we can use immunotherapy effectively,” Tawbi added.

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 tumors. They suggest the findings might be used to build a novel risk-stratification tool for better utilizing immunotherapies in sarcoma patients.