B Cells, Tertiary Lymphoid Structures Promote Cancer Immunotherapy Responses

By Will Boggs MD

January 21, 2020

NEW YORK (Reuters Health) - B cells and tertiary lymphoid structures (TLS) play key roles in promoting cancer immunotherapy responses, according to results from three studies published in Nature.

"T cells are not the only cells involved in cancer control and response to immunotherapy," Dr. Wolf H. Fridman from Centre de Recherche des Cordeliers, Universite de Paris, told Reuters Health by email. "TLS, as factories of antitumor immunity, and B cells can be essential and should be included when deciding on an immunotherapy treatment."

In one of the studies, Dr. Fridman and colleagues established an immune-based classification on the basis of the microenvironment of soft-tissue sarcomas (STS) and identified five distinct phenotypes.

They found that a high density of B cells within tertiary lymphoid structures that contain them, along with T cells and follicular dendritic cells, predicted improved survival in patients with STS. Such features were also associated with a high response rate to PD1 blockade with pembrolizumab in a phase 2 clinical trial.

"It might become a disease-changing approach for patients with STS by selection of patients to be treated by immunotherapy based on the presence of B-cell rich TLS," Dr. Fridman said. "A prospective trial to address this question is underway."

Two other studies examined the role of B cells and TLS in patients with melanoma. Dr. Goran Jonsson from Lund University Cancer Center in Sweden and colleagues found that a gene signature associated with TLS predicted clinical outcomes in patients treated with immune checkpoint blockade.

They also identified distinct subsets of B cells at different stages of development within TLS that could play a role in the response to immune checkpoint blockade, although further studies are needed to confirm this role.

"Our data provide evidence that TLSs may have a key role in sustaining an immune-responsive microenvironment," the authors conclude. "This finding opens avenues for therapeutic strategies that aim at enhancing TLS formation and function, which could result in improved clinical outcomes and responses to cancer immunotherapy."

Dr. Beth A. Helmink from The University of Texas MD Anderson Cancer Center, Houston, Texas, and colleagues performed bulk RNA sequencing of melanomas and found that B cell markers were the most differentially expressed genes in the tumors of responders to immune checkpoint blockade versus nonresponders.

B cells were localized within TLS, and switched memory B cells were enriched in the tumors of responders.

"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," they explain. "Memory B cells may be acting as antigen-presenting cells, driving the expansion of both memory and naive tumor-associated T cell responses."

"B cells can also secrete an array of cytokines (including TNF, IL-2, IL-6 and IFNgamma), through which they activate and recruit other immune effector cells, including T cells," they add. "The observation of switched memory B cells (that can differentiate into plasma cells) in responders suggests that they could be potentially contributing to the antitumor response by producing antibodies against the tumors."

Dr. Hussein A. Tawbi from MD Anderson, who co-authored the first and third papers, told Reuters Health by email, "The fact that this finding is consistent across multiple tumors, which have very different immunobiology, confirms the biological relevance and significance of those findings, and demonstrates that B cells are potentially critical for cancer immunotherapy."

SOURCE: https://go.nature.com/374dz97, https://go.nature.com/365lzFw, https://go.nature.com/30C0EIX Nature, online January 15, 2020.