Landscape of immune checkpoint blockade-induced immune alterations in the microenvironment of primary and metastatic brain tumors

Brain tumors reside in an immune privileged microenvironment where inflammatory processes are heavily regulated. Nevertheless, our recent study showed a significant immune infiltration in recurrent glioblastoma (rGBM) treated with neoadjuvant PD-1 checkpoint blockade therapy. Compared to GBM, the intracranial immunotherapy response of brain metastases (BrM) has been much less studied. Therefore we studied the effect of pre-surgical immune checkpoint blockade (ICB) on the immune compartments of BrM, using multiplex immunofluorescence, mass cytometry and single-cell RNA sequencing. ICB induced much higher T cell infiltration in BrM compared to rGBM. It also caused the loss of a unique perivascular macrophage subset (CD206+LYVE1+), the absence of which associated with the enhanced T cell infiltration in BrM. These T cells produced high levels of IFN-γ that elicited and interferon response transcriptional program in the tumor-associated myeloid cells. T cell-myeloid interactions were also strengthened by ICB in BrM and might have led to the terminal exhaustion of the infiltrating T cells. Our results emphasize the importance of adopting novel immune-boosting approaches to rejuvenate the systemic T cell pool so as to improve tumor control of brain metastases. We processed a total of 18 single cell transcriptomes of metastatic brain tumors with/without prior immune checkpoint blockade treatment. One of the sample, LB3935T, was excluded from the combined counts matrix and subsequent integrated analysis, due to low cell number (<=100 cells).