Differentiation fate of a stem-like CD4 T cell controls immunity to cancer

Maria A. Cardenas, Nataliya Prokhnevska, Ewelina Sobierajska, Petra Gregorova, Christopher B. Medina, Rajesh M. Valanparambil, Rachel Greenwald, Luke DelBalzo, Mehmet Asim Bilen, Shreyas S. Joshi, Vikram M. Narayan, Viraj A. Master, Martin G. Sanda and Haydn T. Kissick ()
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Maria A. Cardenas: Emory University School of Medicine
Nataliya Prokhnevska: Emory University School of Medicine
Ewelina Sobierajska: Emory University School of Medicine
Petra Gregorova: Emory University School of Medicine
Christopher B. Medina: Emory University School of Medicine
Rajesh M. Valanparambil: Emory University School of Medicine
Rachel Greenwald: Emory University School of Medicine
Luke DelBalzo: Emory University School of Medicine
Mehmet Asim Bilen: Emory University School of Medicine
Shreyas S. Joshi: Emory University School of Medicine
Vikram M. Narayan: Emory University School of Medicine
Viraj A. Master: Emory University School of Medicine
Martin G. Sanda: Emory University School of Medicine
Haydn T. Kissick: Emory University School of Medicine

Nature, 2024, vol. 636, issue 8041, 224-232

Abstract: Abstract The T cell response to cancer controls disease progression and response to immunotherapy1–3. Despite extensive knowledge regarding CD8 T cells, how CD4 T cells contribute to this process is less well understood. Here we identified a population of PD1+TCF1+ CD4 T cells with stem-like properties that are capable of self-renewal and differentiation into canonical CD4 effector cells. Primarily residing in tumour-draining lymph nodes (TDLNs), these tumour-specific CD4 T cells are restricted by T regulatory (Treg) cells to a stem-like fate that predominantly generated induced Treg (iTreg) cells, limiting effector CD8 T cell responses to the tumour. By contrast, upon Treg depletion, stem-like CD4 T cells differentiated into T helper 1 (TH1) cells, and via IFNγ production induced robust effector differentiation from TCF1+ CD8 T cells in TDLNs, a state we defined as ‘active’. Notably, enforcing TBET expression in transferred stem-like CD4 T cells was sufficient to overcome the established restricted T cell state. Despite the presence of Treg cells, endogenous stem-like CD4 T cells actively generated TH1 cells, which were required to restore TDLN effector CD8 T cell differentiation, enhance tumour control and rescue response to immunotherapy. In agreement, TH1 differentiation in patients with kidney cancer predicted successful immunotherapy responses and improved progression-free survival. Together, these findings identify a stem-like CD4 T cell population that through alternative differentiation fates controls the switch between restricted and active T cell states with implications for cancer immunotherapies.

Date: 2024
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DOI: 10.1038/s41586-024-08076-7

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