Researchers at the University of Texas MD Anderson Cancer Center used a lot of single-cell analysis to make a spatial map of tumor-infiltrating plasma cells and B cells in early-stage lung cancers. This map shows how these immune cells play roles in the growth of tumors and how well treatments work that were not known before.
The research, which was just published in Cancer Discovery, is the largest and most thorough single-cell atlas on tumor-infiltrating B cells and plasma cells to date. It can be used to create new immunotherapy plans.
“Although we are aware that the tumor microenvironment is crucial in controlling tumor growth and metastasis, our knowledge of these interactions is still limited. T cells have received the majority of attention thus far, “said Linghua Wang, M.D., Ph.D., associate professor of genomic medicine and co-corresponding author. Our research fills in an important gap in what we know about the phenotypes of plasma cells and B cells, which are both important for the early development of lung cancer.
The percentage of lung cancers that are discovered in their early stages has increased thanks to improved screening methods. Although surgery can cure some patients, many still experience a recurrence of their illness, necessitating new therapeutic strategies. Understanding how cancer cells and immune cells work together early on could help find ways to stop the spread of cancer or make the immune system’s defenses stronger against it.
In earlier studies co-led by Wang and her colleagues, B lineage cells were found to be essential for melanoma patients’ responses to immunotherapy. In addition, a study co-led by Wang and Humam Kadara, Ph.D., associate professor of Translational Molecular Pathology, discovered that early-stage lung cancers had an enrichment of B cells and plasma cells in comparison to healthy lung tissue. Plasma cells, or terminally differentiated B cells, are in charge of producing antibodies.
The researchers studied 16 tumors and 47 matched normal lung tissues using single-cell analysis to learn more about the functions of these cells in the early development of lung cancer. Ansam Sinjab, Ph.D., from the Kadara laboratory, Dapeng Hao, Ph.D., and Guangchun Han, Ph.D., from the Wang laboratory, were in charge of the analysis.
The researchers performed single-cell RNA sequencing to examine the gene expression profiles of approximately 50,000 distinct B cells and plasma cells. They also did single-cell B cell receptor sequencing on more than 70,000 cells to learn more about the repertoires of B cell receptors. B cell receptors are membrane-bound proteins on the cell surface that recognize antigens.
The research found 12 different types of cells. More differentiated cell states, like memory B cells and plasma cells, were much more common in tumors than in normal tissue nearby.
According to Kadara, a co-corresponding author on the study, “this level of detailed analysis highlights the dynamic interplay between the tumor and its surrounding immune microenvironment.” Our results show how important environmental factors, like being around cigarette smoke, and molecular features of the tumor are in determining where B cells and plasma cells come from and where they go.
For instance, compared to non-smokers, smokers’ tumors had higher plasma cell counts and lower B-cell clonality. Also, lung tumors with EGFR mutations had more B cells that were not fully developed and fewer plasma cells than lung tumors with KRAS or other mutations.
The researchers also showed that the majority of B cells and plasma cells were recruited to sites with high levels of CXCL13 by analyzing the single-cell data along with spatial information from the tumors. This signaling molecule rises as tumors change from precancerous lesions to invasive lung cancer.
In early-stage lung cancers, the variety of B cells and plasma cells within the tumor also seems to have an impact on patient outcomes and therapeutic responses. Responses to anti-PD-1/PD-L1 immune checkpoint inhibitors and an increase in plasma cells in the tumor were found to have the strongest link to longer survival.
Our in-depth analysis reveals the heterogeneous nature of these cells and their crosstalk with other elements of the tumor microenvironment, Wang said. “Most prior studies have treated tumor-infiltrating B cells or plasma cells as a homogeneous population,” he added. Although more research is required to fully understand their roles in tumor pathogenesis, the evidence suggests that the plasma cell signature could be a useful biomarker for anticipating the results of immunotherapy. “Our findings can be used to find new immunotherapy targets that concentrate on tumor-infiltrating plasma cells and B cells.”
Future research will build on what was learned in this study to find out exactly what role plasma cells and B cells play in the development of early lung tumors and which treatments work best.
This study was paid for by the National Cancer Institute (RP220101, RP160668), MD Anderson, Johnson & Johnson, the Cancer Prevention and Research Institute of Texas, and the National Cancer Institute (R01CA205608, U01CA264583, 1U2CCA233238, P50CA070907, P50CA016672, T32CA217789).
