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

Highlights

• Checkpoint blockade induces transcriptional changes in PD-1⁻CD8⁺ and PD-1⁺CD8⁺ TILs

• PD-1⁻CD8⁺ TILs contain naive-, memory-precursor-, and effector-like subsets

• Memory-precursor- and effector-like PD-1⁻CD8⁺ TILs expand upon checkpoint blockade

• Tcf7 is required for memory-precursor-like cells and efficacy of immunotherapies

Summary

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 after 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 naive-, 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.