A significant step has been made away from the guess-and-check approach to using immune checkpoint blockade therapies to treat non-small cell lung cancer (NSCLC) towards personalization of treatment. Using a range of transcriptomics techniques, such as single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics, the NSCLC tumor microenvironment was characterized, with a focus on a component known as tertiary lymphoid structures (TLSs). This approach yielded new insights into distinct cellular and molecular components that correspond to NSCLC immune checkpoint blockade and chemo-based therapeutics responsiveness. These findings, described in a recent Nature Genetics study, will help future customized neoadjuvant immuno-chemotherapy.
Cracking the NSCLC microenvironment
The use of immune checkpoint blockade has revolutionized the treatment of non-small cell lung cancer (NSCLC), and it has even been found to cure some advanced cases. When this treatment is coupled with chemotherapy (i.e., neoadjuvant immuno-chemotherapy), it becomes even more effective, leading to a much higher rate of major pathological response (MPR). However, many patients still show resistance, and the causes of this are unclear. Studies have demonstrated that immune checkpoint blockade enhances the antitumor immune response by allowing more CD8+ T cells to infiltrate the tumor. However, the tumor microenvironment, crucial for cancer progression and immune evasion, continues suppressing, reducing the therapy’s capacity to be effective in the long run.
TLSs are a major contributor to the tumor microenvironment’s suppression of the antitumor response. Although TLSs are essential for immune cell activation and linked to better outcomes in solid tumors and immune checkpoint blockade response, little is known about how these structures interact with immune cells. Researchers from the labs of An Zeng, Lele Zhang, Yi Eve Sun, Chenfei Wang, and Peng Zhang hypothesized that while scRNA-seq can reveal tumor microenvironment diversity, it lacks spatial information, making it difficult to study cell interactions and structures like TLSs.
Spatiotemporally resolved NSCLC treatment resistance
This study examined single-cell transcriptomes from 232,080 cells and spatially-resolved transcriptomes from tumors of 19 NSCLC patients pre- and post-neoadjuvant immuno-chemotherapy. This approach identified previously undescribed cellular states and spatial patterns linked to inadequate therapeutic response and elucidated the role of TLSs in treatment resistance. The combination of these transcriptomic tools found that tumor cells and specific macrophages interact with cancer-associated fibroblasts to produce collagen barriers at tumor edges, hindering T-cell infiltration and leading to poor outcomes. Distinct states of TLSs were identified, with activated TLSs linked to a better prognosis, while hypoxic conditions suppressed TLS development and were associated with worse outcomes.
By providing crucial new information about the cellular and molecular factors influencing how NSCLC reacts to neoadjuvant immuno-chemotherapy, these findings pave the way for more personalized treatments. Furthermore, this research points to the potential of treatments that target several tumor microenvironment constituents, such as TLSs, macrophages, and fibroblasts, and it also points to new directions for combinatorial therapy development.
