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A tweetorial on our recent pre-print. This work started with a basic question about what B cells and T follicular T cells do in lung cancer. We and others saw that lung adenocarcinoma patients with TFHs and GC B cells fare better than patients without, so we investigated. 1/
We developed a model called HELLO where lung tumors express an antigen with epitopes recognized by B cells and CD4 T cells. HELLO tumors triggered responses by tumor-specific B and T cells and these cells became GC B cells and TFH cells. Moreover, tumors had reduced growth. 2/
Knockout studies showed that tumor control required CD4 and CD8 T cells and B cells, and molecules required for B-CD4 T cell interactions (ICOS and CD40). Further, mice w/o T-B interactions there had noTFH cells and reduced effector CD8 T cell responses. 3/
Many have shown the critical importance of IL21 for effector CD8 T cells and IL21 is a signature cytokine for TFH cells. We showed that control over the growth of HELLO tumors was dependent on IL21R and IL21RKO mice had a drop in effector CD8 T cell. In Wt mice 4/
with HELLO tumors, most IL21 was produced by TFH cells. Similar results were seen in other immunogenic tumor models. Critically, IL21 production by CD4 T cells was dependent on B cells. Further, tumor-specific B cells were necessary for immune control over HELLO tumors. 5/
We then asked what happened to tumor-specific CD4 T cells when they recognized neoantigens w/o B cell epitopes. We tested this in a system where neoantigens did not have B cell epitopes and found that the CD4 T cells specific for these Ags could not become TFHs. 6/
Together, these data highlighted the critical role that interactions between tumor-specific B cells and CD4 T cells have in promoting anti-tumor immunity via a TFH-B cell-IL21 axis and the essential role that tumor neoantigens play in driving fate decisions by CD4 T cells . 7/
Does this pathway exist in patients? We think so b/c TFH cells require B-cell recognized neoantigens and we saw correlations between GC B cells-TFH cells and TFH cells correlate w/ better outcomes. Moreover, we believe this provides a novel therapeutic angle: 8/
driving the TFH-B cell-IL21 pathway by providing signals that B cells would normally provide. Additionally, algorithms predicting B cell neoantigens could be useful for tumor vaccine approaches.
Collaboration between us and Joe Craft via @cancuiyale. biorxiv link below. 9/
Collaboration between us and Joe Craft via @cancuiyale. biorxiv link below. 9/
