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Publications of the Week

Neoantigen-Specific CD4+ T Cells in Human Melanoma Have Diverse Differentiation States and Correlate with CD8+ T Cell, Macrophage, and B Cell Function

By April 22, 2022April 25th, 2022No Comments

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This week we profile a recent publication in Cancer Cell from the laboratories of Drs. Joshua Veatch (pictured, left) and Stanley Riddell (right) at Fred Hutch.

Can you provide a brief overview of your lab’s current research focus?

Our current research focus in the lab is understanding the way helper CD4+ T cells are involved in the immune response to human cancer.  CD4+ T cells work indirectly through coordinating the immune responses of other cells, like “killer” CD8+ T cells, Antibody producing B cells, and innate immune cells like macrophages, but how big a role they play in immunity to human cancer, and which interactions with other immune cells are the most important, are not well understood.  We hope to be able to use CD4+ T cells as a tool for targeting cancers that do not respond well to existing immunotherapies.


What is the significance of the findings in this publication?

In our recent publication, we show that only a subset of the CD4+ T cells that are present in human melanoma actually are specific for tumor antigens and that there is another set of cells that are bystanders that don’t recognize tumor cells.  We are confident in our finding that the cells specific for tumor antigens have a particular “signature” of what genes and surface markers they express because several groups have independently validated similar findings using complementary methods (Eric Tran at Providence Portland and Steve Rosenberg at the National Institutes of Health).
We then use this “signature” of CD4+ T cells that recognize tumor antigens to begin to ask questions about what these cells might be doing.  We used a group of 20 melanoma patients and another group of 33 patients with breast cancer, and compared tumors that had mostly CD4+ T cells with the signature of tumor-specific cells to tumors that had mostly CD4+ T cells that looked like nonspecific “bystanders”.  We found in both groups that the frequency of CD4+ T cells that looked to be specific for tumor antigens correlated with activation of other cell types in the tumor microenvironment: CD8+ T cells, macrophages, and B cells.  In the case of the melanoma patients where we had a longer-term follow-up, we found that the presence of these cells correlated with better outcomes. This suggests the possibility that these tumor-specific CD4+ T cells are performing a useful role in activating other immune cells to combat tumors.


What are the next steps for this research?

We plan to develop strategies to use CD4+ T cells as tools to activate immune cells in the tumor microenvironment, with the goal of helping patients that currently don’t benefit from immune therapies such as immune checkpoint inhibitors.  The idea is to talk to a tumor without a good immune response and transfer large numbers of tumor-specific CD4+ T cells into that patient, and then ask whether this changes the other cells in the tumor in the ways we would expect and whether it can have synergy with immune checkpoint inhibition.  Our first approach to doing this will be using a T cell receptor that allows CD4+ T cells to recognize tumors with the common BRAF V600E mutation.  We are developing a clinical trial targeting this mutation that we hope will be open and treating patients within the next 1-2 years.


If you’d like us to mention your funding sources, please list them.

We had funding from the National Institutes of Health and a grant from the Harry J. Lloyd Charitable Trust.


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