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

Summary An improved understanding of the anti-tumor CD8+ T cell response after checkpoint blockadewould enable more informed and effective therapeutic strategies. Here we examined the dynamics of the effectorresponse of CD8+ tumor-infiltrating lymphocytes(TILs) after checkpoint blockadetherapy. Bulk and single-cell RNA profiles of CD8+ TILs after combined Tim-3+PD-1 blockadein preclinical models revealed significant changes in the transcriptional profile of PD-1 − TILs. These cells could be divided into subsets bearing characterstics of naive-, effector-, and memory-precursor-like cells. Effector- and memory-precursor-like TILs contained tumor-antigen-specific cells, exhibited proliferative and effectorcapacity, and expanded in response to different checkpoint blockadetherapies across different tumor models. The memory-precursor-like subset shared features with CD8+ T cells associated with response to checkpoint blockadein 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.