Lymph Node Fibroblasts May Suppress T-Cell Function in DLBCL

The immunosuppressive role of fibroblastic reticular cells (FRCs) in diffuse large B-cell lymphoma (DLBCL) is detailed in new research published in The Journal of Clinical Investigation.

According to the study’s authors, these findings could have implications for disease pathogenesis and for optimizing immunotherapy in patients with DLBCL.

The disease has 2 molecular subtypes: germinal center (GC) B cell like (GCB) and activated B– cell like (ABC), they noted. Patients with the ABC subtypes tend to have worse outcomes.

In addition, it’s estimated DLBCL is incurable for around 40% of patients for whom treatment with standard rituximab-cyclophosphamide-hydroxydaunorubicin-Oncovin-prednisone (R-CHOP) immunochemotherapy fails.

“FRCs play a dual role in enhancing T-cell activation while also restraining excessive T-cell inflammation via the expression or release of inhibitory molecules to prevent immunopathology,” the researchers explained.

Lymphoid organs tend to have compartmentalized T cells, B cells, and myeloid cells that are ordered into niches to create effective immune responses. FRCs provide structural integrity to these niches and regulate innate and adaptive immune responses during immune activation and homeostasis, the authors explained.

They also direct immune responses through the secretion of cytokines and chemokines and other functions. However, “the immunomodulatory role of fibroblasts in lymphoma is poorly defined,” the authors said.

To better understand the phenotypical, transcriptional, and functional consequences for FRCs exposed to DLBCL, the investigators assessed human and mouse DLBCL lymph nodes.

Imaging mass cytometry was used to analyze a tissue microarray that had 53 patient lymph nodes. Nonmalignant reactive lymph nodes were used as controls.

The investigators found that exposing lymph node–resident immunologically specialized FRCs to DLBCL B cells activated the FRCs and triggered their remodeling and reprogramming.

Exposing the FRCs to DLBCL also led to a change in the cells’ immunoregulatory state. Specifically, they transformed from homeostatic to inflammatory chemokine expression. The FRCs’ altered state after exposure also included upregulated adhesion and antigen-presentation molecules, the authors wrote.

“Our functional studies suggest that altered DLBCL-FRCs impeded optimal T-cell migration and inhibited CD8+ T-cell lytic function,” they added. “Despite these suppressive properties, we demonstrate that FRCs in lymphoma TMEs [tumor microenvironments] can be cotargeted in combination with immunotherapy to boost TIL [tumor-infiltrating lymphocyte] cytolytic activity.”

They also carried out functional assays that revealed the activated FRCs inhibited the optimal migration of TIL and chimeric antigen receptor T cells. What’s more, imaging mass cytometry of patient lymph nodes showed unique environments that differed in their CD8+ TIL-FRC makeup and spatial organization. These factors were associated with survival outcomes.

“We further demonstrated the potential to target inhibitory FRCs to rejuvenate interacting TILs,” the authors wrote.

By cotreating organotypic cultures with fibroblast activated protein (FAP)–targeted immunostimulatory drugs and glofitamab, the researchers found this combination led to augmented antilymphoma TIL cytotoxicity.

Overall, results show “signals from DLBCL B cells activate FRCs and lead to reprogramming of key inflammatory and immunomodulatory pathways,” researchers said. Their findings revealed lymphoid tissues with DLBCL cells had an expanded and remodeled FRC network, which was similar to an amplified acute immune response state, they added.

More research is needed to understand the full breadth of immunoregulatory activity directed by FRCs in different lymphomas, authors noted. They also hypothesize DLBCL-FRCs could modulate additional immune subsets within the TME.

“Additional studies will be required to understand how FRC activation states (as well as other lymph node stromal cells) influence the immune landscape within evolving lymphoma TMEs,” the researchers concluded.

Reference

Apollonio B, Spada F, Petrov N, et al. Tumor-activated lymph node fibroblasts suppress T cell function in diffuse large B cell lymphoma. J Clin Invest. Published online May 23, 2023. doi:10.1172/JCI166070