IFNγ-Induced PD-L1+MHCII+ Macrophages and Tim-3+ Tumor-Reactive CD8+ T Cells Predict a Response to Anti–PD-1 Therapy in Tumor-Bearing Mice

Abstract Although immune checkpoint inhibitors have led to durable responses in various cancer types, a substantial proportion of patients do not respond to these interventions. To uncover potential factors associated with a positive response to immunotherapy, we used a bilateral tumor model with P815 mastocytoma implanted in DBA/2 mice. In this model, only a fraction of tumor-bearing mice responds to anti–PD-1 treatment. Thus, it provides a valuable model to explore the influence of the tumor microenvironment (TME) in determining the efficacy of immune checkpoint blockade–based immunotherapies. It also allows for the analysis of a pretreatment tumor and inference of its treatment outcome based on the response observed in the contralateral tumor. In this study, we report that tumor-reactive CD8+ T-cell clones expressing high levels of Tim-3 are associated with a positive antitumor response following anti–PD-1 administration. Our study also revealed distinct differentiation dynamics in tumor-infiltrating myeloid cells in responding and nonresponding mice. An IFNγ-enriched TME promoted the differentiation of monocytes into PD-L1posMHCIIhigh cells in mice responding to immunotherapy. Monocytes present in the TME of nonresponding mice failed to reach the same final stage of differentiation trajectory, suggesting that an altered monocyte-to-macrophage differentiation route may hamper the response to immune checkpoint blockade. These insights will direct future research toward a temporal analysis of tumor-associated macrophages, aiming to identify factors responsible for transitions between differentiation states within the TME. This approach may pave the way for novel strategies to enhance the efficacy of PD-1 blockade.