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^1-3. 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_H1) 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_H1 cells, which were required to restore TDLN effector CD8 T cell differentiation, enhance tumour control and rescue response to immunotherapy. In agreement, T_H1 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.