High-Baseline Tumor Burden–Associated Macrophages Promote Immunosuppressive Microenvironment and Restrain Immune Checkpoint Inhibitor Efficacy Through the IGFBP2–STAT3–PD-L1 Pathway

Background: In recent decades, immune checkpoint inhibitors (ICIs) have become a conspicuous promising treatment. However, there are still some problems such as limited effective rate and undefined suitable patients. With increasing attention to the influence of baseline tumor burden on the therapeutic efficacy of ICIs, most researchers are currently of the view that patients with high-baseline tumor burden (HTB) have shorter overall survival and poor immunotherapy efficacy; nevertheless, recent studies have been limited to clinical phenomena without deep mechanistic exploration. Methods: RNA-seq and Single-cell RNA sequencing were used to reveal the difference of microenvironment between low-baseline tumor burden (LTB) and HTB tumor. Mice model construction, flow cytometry and cytokine antibody array were used to identify the phenomenon and mechanism of HTB effects on tumor immune microenvironment (TIME) and ICIs effcacy.Results: HTB caused a significantly higher infiltration with M2-type macrophages expressing a high level of programmed death-ligand 1 (PD-L1) to block the infiltration by CD8+ T cells and impaired the therapeutic effect of ICIs. HTB-derived IGFBP2 induced the macrophages’ polarization and PD-L1 expression via signal transducer and activator of transcription 3 (STAT3) signaling pathway. Moreover, these HTB–activated macrophages exerted a pro-tumor effect by inhibiting proliferation and cytotoxic function of CD8+ T cells in a PD-L1-dependent fashion. Disappointingly, total tumor burden did not affect the microenvironment or the immunotherapy efficacy of any single tumor. Moreover, macrophage inhibitor in HTB and palliative surgery were not able to increase the therapeutic efficacy in HTB. Only in the early stage of tumor with LTB, the macrophage inhibitor PLX3397 significantly improved the efficacy of ICIs on HTB. Conclusions: Our study has demonstrated that HTB induced the production of PD-L1+ M2-macrophages through the IGFBP2–STAT3 signaling pathway to generate the suppressive TIME, thereby reducing the efficacy of ICIs. These results further clarify the effects and illuminate a novel mechanism of HTB effects on ICI efficacy, and also provide functional evidence for an earlier use of macrophage inhibitors or combination treatment to reshape the tumor microenvironment.