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

The T cell response to cancer controls disease progression and response to immunotherapy 1 , 2 – 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 (T reg ) cells to a stem-like fate that predominantly generated induced T reg (iT reg ) cells, limiting effector CD8 T cell responses to the tumour. By contrast, upon T reg depletion, stem-like CD4 T cells differentiated into T helper 1 (T H 1) 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 T reg cells, endogenous stem-like CD4 T cells actively generated T H 1 cells, which were required to restore TDLN effector CD8 T cell differentiation, enhance tumour control and rescue response to immunotherapy. In agreement, T H 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. A population of tumour-specific PD1 + TCF1 + CD4 T cells in tumour-draining lymph nodes is capable of self-renewal and differentiation into CD4 effector cells, thereby controlling CD8 T cell activity.