Fig. 2.

Losartan prevents ICB-induced edema by downregulating TEC MT-MMP-1 and -2 expression. Losartan decreases anti-PD1-induced edema in (A) GL261 and (B) 005 GSC models but not in (C) CT2A after 2 wk of treatment (n = 5 to 9). (D) scRNASeq of TECs reveals a set of downregulated genes that includes those related to metabolism (e.g., Adh1, Ildr2), angiogenesis/migration (e.g., Cnpy2, Igf1r), and solute carriers (e.g., Slc35f2, Slc19a3). When applied as an edema signature, this gene set is upregulated in anti-PD1-treated GL261 tumors compared to other treatment arms as visualized via (E) volcano plot, (F) density plot of edema signature scores (methods described in SI Appendix) by treatment and (G) mean gene expression heat map of edema signature genes. (H) Specialized MT-MMPs (Mt1, Mt2) are among these genes and are expressed in TECs only from the anti-PD1-treated tumors. (I) The MMP inhibitor Ilomastat (MMPi) controls anti-PD1-induced edema comparably to losartan in GL261 (n = 6). (Edema signaturegene expression units = ln(TP100k + 1); log₂FC = fold changes > |2|; adjusted P value < 0.05. Bar plots: mean ± SEM; one-way ANOVA with Tukey’s post hoc test; *P < 0.05; **P < 0.01; ***P < 0.001.)