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Early-Stage Lung Cancer Development Traced in Single-Cell RNA Sequencing Study

NEW YORK – Using single-cell RNA sequencing, researchers have mapped how lung cells transform into early-stage lung cancer, described cellular intra-tumor heterogeneity, and identified targets for treatment.

In a study published in Cancer Discovery on Monday, researchers led by Ansam Sinjab and Guangchun Han from the University of Texas MD Anderson Cancer Center performed single-cell RNA sequencing of nearly 187,000 cells from five early-stage lung tumors and 14 normal lung tissue samples located at specific distances from the tumor. They aimed to sharpen the resolution of the changes epithelial and other cells in the lung ecosystem undergo as they become cancerous.

Specifically, the researchers created a spatial map of lung cancer tumor cells and normal lung cells. The differences between tumor cells, tumor-adjacent cells, and tumor-distant cells could help identify markers for early detection or prevention.

In the study, the researchers found that normal cells located closer to tumor cells were more like cancer cells than distant non-cancerous cells because the transcriptomes of these tumor-adjacent cells and tumors were similar.

"It is noteworthy that we found, in the normal-appearing samples, cells with features of malignant-enriched subsets and heterogeneous [copy number variation] profiles," the authors wrote. "Whether these cells comprise early [lung cancer] precursors, mutagenic clones that do not progress to malignancy, or putative molecular field cancerization remains to be investigated."

They also analyzed the prevalence of lymphoid cells in tumor and normal tissue. Cells in tumor tissue were enriched for plasma cells, B cells, and T-regulatory cells. Natural killer cells, innate lymphoid cells, and cytotoxic T cells were depleted in tumor tissue. Some of these same features also appeared in normal cells. There was a gradual decrease in the same NK cells, innate lymphoid cells, and cytotoxic T cells in normal tissue the closer it was to the tumor.

Among patients who had smoked, plasma cell fractions were high compared to non-smokers, suggesting that plasma cells could play a role in the development of smoking-associated lung cancer.

In their paper, the authors also described increased interactions between immune checkpoint proteins CD24 or LGALS9 on tumor epithelial cells in multiple patients. In the majority of patients, cell clusters enriched for malignant cells were enriched for CD24 expression. "These findings demonstrate that the early-stage [lung adenocarcinoma] ecosystem harbors cell-cell communication that confers increased pro-tumor inflammatory and immunosuppressive states," the authors wrote.

The researchers used data from external cohorts and found CD24 expression was associated with immune suppressive activity. Data from an in-house cohort of early-stage lung cancer patients who had been analyzed by targeted immune profiling showed that higher CD24 expression was associated with shorter overall survival and progression-free interval.

In a mouse model, the researchers showed that inhibiting CD24 using CRISPR-mediated knockout or neutralizing antibodies "significantly reduced" the growth of lung cancer cells.

"These findings show that CD24, which we found to be at the core of an enriched cell-cell interactome in early-stage [lung cancer], is associated with a pro-tumor immune contexture and poor prognosis, as well as promotes [lung cancer] growth in vivo," the authors wrote.

Together, these findings suggest CD24 is a viable target for early-stage lung cancer treatment, they concluded, adding that they will continue to explore this in future studies.

T regulatory cells that express pro-tumor immune checkpoints, TIGIT and CTLA-4, were also potential immunotherapy targets identified in the study. T cells that expressed these markers were found closer to the tumor, "suggesting a value in combinatorial targeting of multiple checkpoints for immunotherapy," the authors noted.

"This high-resolution spatial mapping generated a much more complete picture of lung cancer than was previously available, and we believe this will be a valuable resource to the research community," co-senior author Linghua Wang, assistant professor of genomic medicine at MD Anderson, said in a statement. "We now have a greater understanding of the tremendous heterogeneity of diverse cell populations within the tumor immune microenvironment and of the importance of tumor-microenvironment interactions in regulating cancer progression."