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Diffuse Large B Cell Lymphoma Tumor, Microenvironment Features Explored With Single-Cell Atlas

NEW YORK – A team from Sweden and China has developed a single-cell transcriptome atlas for diffuse large B cell lymphoma (DLBCL), uncovering expression heterogeneity within and across DLBCL cases, tumor interactions with immune and other microenvironment cells, and features influencing tumor biology, including hepatitis B virus (HBV) infections.

"[W]e showed that the development trajectory of malignant and nonmalignant cells, interplays between malignant and tumor-infiltrating cells, and the influence of chronic viral infection can further explain the disease heterogeneity of DLBCL," co-senior and co-corresponding author Qiang Pan-Hammarström, a biosciences and nutrition research at the Karolinska Institute, and colleagues wrote, noting that "[f]urther investigation of the somatic mutational profile and drug response in the identified sub-population of malignant cells may provide additional insights into the disease mechanism and therapeutic strategies."

As they reported in Cell Reports on Tuesday, the researchers performed droplet-based single-cell RNA sequencing on more than 94,400 individual cells from 17 DLBCL cases, analyzing the single-cell transcriptome data alongside whole-genome sequence and bulk RNA sequence data. They also set these findings against gene expression features found in tumor samples from three individuals with unrelated conditions: Burkitt's lymphoma, follicular lymphoma, or reactive lymphoid hyperplasia.

"[U]sing a single-cell RNA sequencing (scRNA-seq) approach, we created a comprehensive cell atlas for malignant and nonmalignant cells in DLBCL, which also enabled us to study the influence of chronic HBV infection on lymphomagenesis at the single-cell level," the authors explained.

Within the malignant DLBCL cells, the team unearthed 73 different gene expression patterns, including eight expression programs that appeared to turn up across the samples considered. Each sample contained between two and seven distinct gene expression patterns, providing clues to the expression and signaling patterns contributing to DLBCL treatment response, relapse, and outcomes.

In the tumor microenvironment, meanwhile, the researchers highlighted eight B cell clusters, 16 T cell clusters, and half a dozen myeloid cell clusters. When they delved into the interplay between tumor cells and microenvironment features using insights from almost 2,800 cell-cell interaction predictions in the atlas, the investigators saw microenvironment signals that seemed to boost tumor cell survival and identified inhibitory T cell features linked to T cell immune exhaustion.

"Because the normal counterpart of B cell lymphoma is also part of the immune system," the authors explained, "the interactions between malignant cells, infiltrated T cells, and other immune cells in the [tumor microenvironment] are therefore more complex to dissect in comparison with other solid tumors."

In a subset of samples marked by HBV infection, the team found gene expression shifts involving major histocompatibility complex class II, interferon-gamma immune activity, and other genes that appeared to alter tumor interactions and outcomes in these cases, despite similar nonmalignant cell compositions in HBV-positive and HBV-free forms of DLBCL.

"Taken together, the results indicate that HBV infection may have a significant impact on both malignant and nonmalignant cells, and, in general, the [tumor microenvironment] is more immunosuppressive in HBV-positive DLBCL patients," the authors reported. "Because a poor response to current first-line immunochemotherapy has been reported for HBV-positive DLBCL patients, our results may provide molecular evidence to support clinical trials on alternative therapeutic strategies for this group of patients, such as combining anti-PD-1 or anti-CTLA with other immune checkpoint inhibitors."