Written by Lauren Robertson, Science Writer.
Researchers from the University of Texas MD Anderson Cancer Center have revealed the largest and most comprehensive spatial atlas of tumour-infiltrating B cells and plasma cells in lung cancer to date.
In a study published in Cancer Discovery, single-cell RNA sequencing was used to map the distribution of these specific immune cells, revealing the vital roles they play in early-stage lung adenocarcinoma development and treatment outcomes – a role not fully appreciated until now.
Less T, more B
In recent years, improved diagnostics has meant lung cancers are being picked up much earlier than ever before. Surgery is often quite effective in removing this cancer, but other treatment options are desperately needed in cases where the tumour re-occurs. Understanding the intricate communication pathways between cancer and immune cells could help scientists to boost the immune response or potentially block cancer growth altogether.
Though lots of work has focused on the role of T cells in tumour progression, B cells have been somewhat overlooked. “We know the tumour microenvironment plays an important role in regulating tumour growth and metastasis, but we have an incomplete understanding of these interactions. So far, most of the focus has been on T cells,” said co-corresponding author Linghua Wang, Associate Professor of Genomic Medicine. “Our study provides much-needed understanding of the phenotypes of B cells and plasma cells, which also play critical roles in early lung cancer development.”
In their previous research together, Linghua Wang and Humam Kadara (co-corresponding author) already demonstrated the important role that B cells play in the immunotherapy responses of melanoma patients. They also found that B cells and plasma cells (B cells that produce antibodies) were enriched in early-stage lung cancers relative to normal tissues. At this point, they decided to shift their focus to creating a detailed atlas of these important cells.
The tumour environment
To get a better idea of what was going on in early-stage lung adenocarcinoma, they performed single-cell analysis on 16 tumours and 47 matched normal lung tissues. Overall, single-cell RNA sequencing data was collected on around 50,000 unique B cells and plasma cells, providing an insight into their gene expression profiles. They also looked at B cell receptors from more than 70,000 cells to understand the different repertoires present.
In total, 12 different cell subsets were identified by the team. Tumours were enriched in memory B cells and plasma cells compared to normal tissue, and these cells also exhibited more differentiated states and somatic hypermutations.
Importantly, the researchers saw the first-hand impact of certain environmental factors on cancer – smokers had elevated plasma cell levels and decreased B-cell clonality. Also, tumours with an EGFR mutation had lower plasma cell levels and higher B cell levels than those with the KRAS mutation. “This level of detailed analysis highlights the dynamic interplay between the tumour and its surrounding immune microenvironment,” said Kadara.
The signalling molecule, CXCL13, also seems to play an important role in recruiting B cells and plasma cells to the tumour site – levels of this molecule seemed to increase as the tumours progressed from pre-cancerous lesions to invasive lung cancer.
What does this mean for treatment outcomes?
As well as providing a detailed spatial map of the B cells and plasma cells involved in lung adenocarcinoma, the study also highlighted that higher levels of plasma cells in the tumour were associated with improved survival and responses to anti-PD-1/PD-L1 immune checkpoint inhibitors. This could have a profound impact on the development of immunotherapies moving forward.
“Most previous studies have treated tumour-infiltrating B cells or plasma cells as a homogeneous population, but our in-depth analysis highlights the heterogeneous nature of these cells and their crosstalk with other components of the tumour microenvironment,” Wang said. “Further studies are needed to fully understand their roles in tumour pathogenesis, but the evidence suggests the plasma cell signature may be a valuable biomarker to predict immunotherapy outcomes. Our findings can also be leveraged to identify new targets for immunotherapy.”
