New studies focus on B cells in lymphoid structures within tumors.

Three recent papers in Nature could help improve cancer treatment by immune checkpoint blockade (ICB). Checkpoint inhibitors such as the antibody therapies ipilimumab, nivolumab, and pembrolizumab promote a response against cancer by blocking CTLA-4, PD-1, or PD-L1. The research behind this therapy was recognized with the 2018 Nobel Prize in Physiology or Medicine.

“We wanted to see if B cells, the other main part of adaptive immunity, have a role in anticancer immunity.”

Göran Jönsson, professor in molecular oncology, Lund University, led one of the studies. “We’ve known for a while that T cells have a crucial function in the anticancer response in melanoma,” he says. “We wanted to see if B cells, the other main part of adaptive immunity, have a role in anticancer immunity.”

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TLS, checkpoint blockade, and survival

The paper by Cabrita et al. focuses on B cells in tertiary lymphoid structures (TLS), which are groups of immune-related cells at inflammation sites, including in tumors. The researchers used melanoma samples and medical records to find that survival was better in patients with tumors that contained active B cells in clusters that expressed TLS markers.

The team studied B cells in tumors using a novel method – digital spatial profiling for high-plex proteomics on fixed tissue samples. Quantitating the types and amounts of 60 proteins allowed the scientists to characterize intratumor structures with B and T cells. Some tumors had areas similar to germinal centers, where B cells divide and mature. Other tumors showed less organization and T cells with a dysfunctional molecular phenotype.

“Some melanomas had the organization and markers of TLS,” Jönsson says. ”And TLS had active populations of B, T and other immune cells. TLS, he hypothesizes, could be where T cells learn to recognize tumor cells or B cells make antibodies against tumors. “The T cells in tumors without TLS,” Jönsson says, “had a more exhausted phenotype.” And this T cell phenotype is linked to poor response to ICB.

 

Göran Jönsson Photo Kennet Ruona

Göran Jönsson, Professor in Molecular Oncology, Medical faculty, Lund University. Photo: Kennet Ruona

Toward better checkpoint blockade

The researchers used differential gene expression analysis to identify an expression signature for melanomas with TLS. With further investigation, including using samples from patients receiving CTLA-4 or PD-1 blockade, Jönsson says, “We found the signature is associated with response to ICB and patient survival.”

The expression signature could be used to predict patients who will likely respond to ICB and to identify new immunotherapy targets. Jönsson’s lab is studying TLS functions using organoids from patient samples. These in vitro structures have cell types, arrangements and activities of specialized tissues. Jönsson says the life science industry is definitely interested in tumor TLS.

“The papers open the possibility to increase the response rates to checkpoint blockade.”

“The papers open the possibility to increase the response rates to checkpoint blockade,” he says. “Maybe by activating B cells we can enhance or promote formation of TLS.”

REFERENCE

Cabrita R, Lauss M, Sanna A, Donia M, Skaarup Larsen M, Mitra S, Johansson I, Phung B, Harbst K, Vallon-Christersson J, van Schoiack A, Lövgren K, Warren S, Jirström K, Olsson H, Pietras K, Ingvar C, Isaksson K, Schadendorf D, Schmidt H, Bastholt L, Carneiro A, Wargo JA, Svane IM, Jönsson G. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature. 2020;577(7791):561-565.

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