NEW YORK – A team from the University of Chinese Academy of Sciences, Tongji University, and other centers in China has unearthed molecular features linked to drug resistance in non-small cell lung cancer (NSCLC) treated with neoadjuvant chemotherapy and immune checkpoint blockade (ICB) immunotherapy prior to surgery, highlighting the importance of tumor interactions with immune cells and immune cell structures in the tumor microenvironment (TME).
"Our study provides novel insights into the complex NSCLC ecosystem and identifies potential biomarkers for future combinatorial therapies," the study's authors wrote in Nature Genetics on Tuesday, noting that the work uncovered "novel insights into different cellular and molecular components corresponding to NSCLC ICB-chemotherapeutic responsiveness."
For their study, the investigators used a combination of single-cell RNA sequencing and 10x Genomics Visium spatial transcriptomics to characterize tumor and tumor microenvironment features in up to 232,080 individual cells in 26 samples collected from 19 individuals with NSCLC before and after neoadjuvant anti-PD-1 ICB and chemotherapy treatment.
"Many patients with NSCLC remain resistant to neoadjuvant immuno-chemotherapy and the molecular mechanisms behind this resistance are still unclear," the authors explained, adding that the current work brought together scRNA-seq and spatial transcriptomics to profile the cellular composition and spatial organization of tumor cells and the microenvironment before and after neoadjuvant ICB-chemotherapy in responders and non-responders.
In the process, the team tracked down treatment response-related features involving both tumor and TME cells, including molecular features that may inform future efforts to curb neoadjuvant immunotherapy-chemotherapy resistance.
"[W]e identified distinct tumor cell features and microenvironment compartments that displayed remarkable heterogeneity and dynamic changes in response to treatment," the authors reported.
When they analyzed the single-cell and spatial transcriptomic data alongside pathology-based measures of ICB-chemotherapy response, for example, the investigators found that cases with poor prognoses tended to have impaired T-cell infiltration stemming from collagen fiber deposits in cells at the tumor boundary — a process involving interactions between collagen type XI alpha 1 chain-positive cancer-associated fibroblasts, tumor cells, and macrophage immune cells that secrete phosphoprotein 1.
The research also pointed to the presence of variable T-cell priming-, B-cell activation-, and T and B cell differentiation-related "tertiary lymphoid structures" in the TME — ranging from prognostically beneficial "activated" TLSs to a hypoxia-related, immunosuppressive state involving muted TLSs and poorer-than-usual NSCLC outcomes.
Together, the authors suggested, the current findings "highlight the potential of therapies that target multiple components of the TME, including fibroblasts, macrophages, and [tertiary lymphoid structures], and suggest new avenues for developing combinatorial therapies."