Differentiation fate of a stem-like CD4 T cell controls immunity to cancer.
Abstract
The T cell response to cancer controls disease progression and response to immunotherapy<sup>1-3</sup>. 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<sup>+</sup>TCF1<sup>+</sup> 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 (T<sub>reg</sub>) cells to a stem-like fate that predominantly generated induced T<sub>reg</sub> (iT<sub>reg</sub>) cells, limiting effector CD8 T cell responses to the tumour. By contrast, upon T<sub>reg</sub> depletion, stem-like CD4 T cells differentiated into T helper 1 (T<sub>H</sub>1) cells, and via IFNγ production induced robust effector differentiation from TCF1<sup>+</sup> 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 T<sub>reg</sub> cells, endogenous stem-like CD4 T cells actively generated T<sub>H</sub>1 cells, which were required to restore TDLN effector CD8 T cell differentiation, enhance tumour control and rescue response to immunotherapy. In agreement, T<sub>H</sub>1 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.
EDRN PI Authors
- (None specified)
Medline Author List
- Bilen MA
- Cardenas MA
- DelBalzo L
- Greenwald R
- Gregorova P
- Joshi SS
- Kissick HT
- Master VA
- Medina CB
- Narayan VM
- Prokhnevska N
- Sanda MG
- Sobierajska E
- Valanparambil RM