Fibroblastic reticular cells power immune defenses in lung cancer

Discover how specialized cells form immune-boosting niches in lung tumors, unlocking new strategies to enhance cancer treatments and improve outcomes.

Study: Fibroblastic reticular cells generate protective intratumoral T cell environments in lung cancer. Image Credit: CI Photos / Shutterstock.com

In a recent study published in the journal Cell, researchers investigate the role of fibroblastic reticular cells (FRCs) in creating T-cell-supportive niches within lung cancer tumors. The study findings elucidate how these specialized cells contribute to immune defenses by forming interconnected environments that facilitate T-cell activity, potentially enhancing anti-tumor immunity in non-small cell lung cancer (NSCLC).

What are FRCs?

The ability of the immune system to fight cancer relies on coordinated interactions between various immune cells and their specialized microenvironments.

Tumor-infiltrating lymphocytes, for example, are critical for anti-tumor immunity; however, their activity is dependent on local niches that sustain their functions. These niches often resemble structures in lymphoid organs, such as tertiary lymphoid structures, which are enriched with immune cells and associated with favorable outcomes in cancer.

FRCs are essential components of lymphoid organs that provide structural support and secrete factors that guide immune cells. FRCs also promote T-cell migration, survival, and differentiation.

Although FRCs are well-studied in lymphoid tissues, their presence and role within tumors remain unclear. Thus, understanding how FRCs create T-cell-friendly environments within tumors is crucial to clarify the different mechanisms that may boost immunity and improve therapeutic responses. To date, there remains a lack of data on the origin, differentiation pathways, and specific contributions of FRCs to tumor immunity.

About the study

In the present study, researchers utilize various advanced techniques, including single-cell ribonucleic acid (RNA) sequencing, high-resolution microscopy, and cell fate mapping to investigate FRCs in NSCLC and experimental murine models.

Human tumor samples were initially used to identify the distribution and phenotype of FRCs. Immunohistochemical staining revealed the presence of FRCs expressing C-C motif chemokine ligand 19 (CCL19) in tumor-associated niches, such as tertiary lymphoid structures and T-cell tracks. These structures were further examined for their involvement in immune cell interactions and T-cell activity.

In vivo, studies in mice were subsequently conducted to monitor the differentiation of FRCs from perivascular progenitor cells through lineage-tracing methods. Thereafter, two distinct FRC subsets of perivascular reticular cells and T zone reticular cells were found to originate from adventitial and mural fibroblast populations. The spatial organization of these FRC subsets was analyzed through confocal microscopy to elucidate their role in creating pathways for T-cell migration and clustering within tumors.

A coronavirus vector-based immunotherapy model was also used to assess how FRC networks enhance immune cell recruitment and activity. Additionally, FRC ablation or inactivation was performed in mice to determine their role in maintaining intra-tumoral T-cell populations and promoting tumor control. Various bioinformatics analyses were also employed to identify molecular pathways involved in FRC-mediated immune regulation.

Study findings

FRCs play a pivotal role in promoting anti-tumor immunity within lung cancer by forming interconnected T-cell environments. These specialized cells, which were identified in both human tumors and mouse models, establish niches resembling lymphoid organ structures, including tertiary lymphoid structures and T-cell tracks.

In human NSCLC, CCL19-expressing FRCs were responsible for tertiary lymphoid structure formation and T-cell tracks. These structures facilitated T-cell clustering, which suggests enhanced immune interactions within the tumor microenvironment. Confocal microscopy also revealed CCL19 gradients along T-cell tracks that likely facilitate T-cell migration and activation.

In mice, lineage tracing demonstrated that FRCs differentiate from distinct progenitor cells located in perivascular spaces. Both FRC subsets of perivascular reticular cells and T-zone reticular cells were found to be critical for maintaining these immune niches and supporting T-cell recruitment, survival, and activation through the secretion of migration cues, growth factors, and chemokines.

Experiments using a coronavirus vector-based immunotherapy model further revealed that inducing FRC-supported tertiary lymphoid structures enhanced immune cell infiltration and anti-tumor activity. Additionally, ablation of FRCs led to diminished T-cell presence and reduced tumor control, thus reflecting their essential role in immune defense.

The bioinformatics analyses identified key molecular pathways mediated by FRCs, including those involving chemokines such as C-X-C motif chemokine ligand (CXCL)12 and CXCL16, as well as adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1).

Conclusions

FRCs provide the structural and functional foundations for intra-tumoral immune environments by facilitating T-cell migration, clustering, and activation. These findings highlight the potential of FRCs as therapeutic targets to enhance anti-tumor immunity by promoting the formation and function of T-cell-supportive niches.