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. 2019 Apr 30;116(22):10674–10680. doi: 10.1073/pnas.1819889116

Fig. 3.

Fig. 3.

Tumor-targeted ARBs normalize the tumor microenvironment to a greater degree than free ARBs. (A–E) Histological and biomechanical analysis of orthotopic MCa-M3C breast tumors in mice treated with free ARB, TMA-ARB, or saline (control). (A) Tumor αSMA+ cell area fractions. TMA-ARB treatment reduced αSMA+ cell (primarily CAF) density (*P = 0.037). n = 6–7. (B) Tumor collagen I area fractions. Both free ARB treatment (*P = 0.032) and TMA-ARB treatment (**P < 0.01) reduced tumor collagen I expression. n = 5–8. (C) Relative tumor solid stress levels. Both free ARB treatment (*P = 0.032) and TMA-ARB treatment (**P < 0.01) reduced solid stress, with the TMA-ARB reducing it more (***P = 0.05). n = 10–11. (D) Fractions of tumor blood vessels with open lumen, indicating the extent of vessel decompression. Both free ARB treatment (*P < 0.01) and TMA-ARB treatment (**P < 0.01) decompressed blood vessels, with the TMA-ARB most effective (***P < 0.01). n = 4. (E) Tumor blood vessel density. n = 4. (F–I) Gene expression (qRT-PCR) and cell population (flow cytometry) analysis in whole tumors or cell populations sorted from orthotopic breast tumors in mice treated with free ARB, the TMA-ARB, or saline (control). (F) Confirmation of hits from a gene expression array in whole MCa-M3C tumors. Treatment with the ARB decreased Cxcl13 expression (P < 0.05), while treatment with the TMA-ARB decreased Cxcl13 expression (P < 0.05) and Fasl expression (P < 0.05) in whole tumors. n = 5–8. (G) Gene expression in αSMA+ cells sorted from E0771 tumors. Treatment with the TMA-ARB decreased Cxcl13 and Fasl expression in these sorted cells (P < 0.05). n = 3–4. (H) Gene expression in CD45+CD3-B220+ B lymphocytes sorted from E0771 tumors. Treatment with the ARB or TMA-ARB decreased expression of genes associated with immunosuppression and autocrine stimulation (P < 0.05). n = 3. (I) Gene expression in CD45+CD3+CD8+ cytotoxic T lymphocytes sorted from E0771 tumors. Treatment with the ARB or TMA-ARB increased expression of several genes associated with cytotoxic T cell activity (P < 0.05). n = 3–4.