Checkpoint Blockade Immunotherapy Induces Dynamic Changes in PD-1−CD8+ Tumor-Infiltrating T Cells

An improved understanding of the anti-tumor CD8(+) T cell response after checkpoint blockade would enable more informed and effective therapeutic strategies. Here we examined the dynamics of the effector response of CD8(+) tumor-infiltrating lymphocytes (TILs) after checkpoint blockade therapy. Bulk and single-cell RNA profiles of CD8(+) TILs following combined Tim-3+PD-1 blockade in preclinical models revealed significant changes in the transcriptional profile of PD-1(−) TILs. These cells could be divided into subsets bearing characterstics of naïve-, effector-, and memory-precursor-like cells. Effector- and memory-precursor-like TILs contained tumor-antigen specific cells, exhibited proliferative and effector capacity and expanded in response to different checkpoint blockade therapies across different tumor models. The memory-precursor-like subset shared features with CD8(+) T cells associated with response to checkpoint blockade in patients, and was compromised in the absence of Tcf7. Expression of Tcf7/Tcf1 was requisite for the efficacy of diverse immunotherapies, highlighting the importance of this transcriptional regulator in the development of effective CD8(+) T cell responses upon immunotherapy.