Saying HELLO to TFH cells

The problem

One of the strongest clinical observations in lung cancer is that patients with tertiary lymphoid structures (TLS) in their tumors tend to do better. Even more striking, patients whose TLS contain germinal centers (GCs) — the specialized sites where B cells and TFH cells interact — have the best outcomes. For years this has been a reproducible finding across studies, but the mechanism has been unclear. Why would the presence of germinal centers make such a difference? Are B cells or TFH cells actively shaping the anti-tumor response, or are these structures simply a byproduct of strong immunity?

Our lab has long been interested in how immune niches — lymph nodes, TLS, and other organized aggregates — support T cell responses. CD8 T cells are the main cytotoxic killers in tumors, but they don’t operate in isolation. In infections, we know that CD8 T cells depend on CD4 T cell “help,” and in humoral immunity, TFH cells are indispensable for generating high-quality antibody responses. But whether TFH cells matter in cancer — and specifically whether they do more than just support B cells — had never been tested. This was the open question: Do TFH cells in tumors play an active role in anti-tumor immunity, and could that explain why TLS with germinal centers predict better outcomes?

A new tool: the HELLO system

Answering this required a model where B cells, TFH cells, and CD8 T cells could all engage the same tumor antigen. Existing models didn’t allow this, so we built one. We designed the HELLO system — a synthetic antigen that contained both B cell and T cell epitopes — and introduced it into genetically engineered lung cancer models. With this tool, we could directly test how B cell recognition of tumor antigens shaped the development of TFH cells, and whether that in turn affected CD8 T cell function.

Saying HELLO to TFH cells

The HELLO tumors revealed a clear story. When B cells could recognize the tumor antigen, they drove the development of TFH cells. Those TFH cells, in turn, produced IL-21, a cytokine known to influence many lymphocyte populations. The effects of IL-21 were dramatic: CD8 T cells in these tumors expressed more granzyme, sustained cytolytic function, and controlled tumor growth more effectively. When IL-21 was missing, CD8 T cells rapidly lost activity and tumors progressed faster. Crucially, restoring IL-21 by transferring CD4 T cells that could produce it rescued CD8 T cell function.

What it means

This work provided the first direct evidence that TFH cells support CD8 T cells inside tumors. It explained why TLS that contain germinal centers — and therefore TFH cells — correlate with better outcomes, while TLS without GCs do not. It reframed our understanding of “help” in tumor immunity: CD4 T cell help is not limited to priming dendritic cells, but extends to direct TFH–B–CD8 cooperation inside tumor-associated lymphoid structures.

These findings have several implications. They give a mechanistic explanation for why TLS composition predicts prognosis, connecting human observations to experimental biology. They highlight IL-21 as a critical cytokine for sustaining anti-tumor CD8 responses, raising the possibility of new therapeutic strategies to amplify this pathway. And more broadly, they demonstrate how the architecture of the immune system — the physical spaces where cells meet and the partners they find there — can be as important as the cells themselves.