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. 2020 Oct 19;130(11):6109–6123. doi: 10.1172/JCI135528

Figure 2. Anti-SIRPα synergizes with anti–PD-L1 and anti–4-1BB mAbs and prevents T cell exclusion.

Figure 2

(A) Tumor volume in MC38 model of mice treated i.p. triweekly (days 4–28) with control (black, n = 6), MY1-G1 anti-SIRPα (blue, 10 mg/kg, n = 13), anti–PD-L1 (10F-9G2, open green triangle, 6 mg/kg, n = 12), or MY1-G1 plus anti–PD-L1 (filled green triangle, n = 28) mAbs. (B) Survival of untreated naive (black, n = 7) or MC38 tumor-free mice treated with the anti-SIRPα+PD-L1 combination (green, n = 10) and rechallenged with MC38 cells 2 months after first tumor inoculation. (C) Survival in the Hepa1.6 HCC orthotopic model of mice treated i.p. (days 4–28) triweekly with control (black, n = 48), P84 anti-SIRPα (red, 10 mg/kg, n = 48), anti–PD-L1 (open green triangle, 6 mg/kg, n = 14), or P84+anti-PDL-1 (filled green triangle, n = 18) mAbs. Some mice received 2 injections (days 4 and 8) of 3 mg/kg 3H3 (4-1BB agonist; open blue circle, n = 15) alone or in combination with P84 (filled blue circle, n = 15). Three independent experiments are represented. (D) Survival of untreated naive or Hepa1.6-cured mice rechallenged with intrasplenic Hepa 1.6 cells 3 to 4 months after first tumor inoculation. Symbols are the same as in C. (E) Survival of untreated mice implanted with Hepa 1.6 cells in the portal vein after adoptive transfer of 10 × 106 splenocytes or 2.5 × 106 spleen T cells isolated from cured mice in D. (F) Same as in E after adoptive transfer of 200 μL of plasma from PD-L1/SIRPα-cured mice. (G) T cell infiltrates histological quantification in the entire tumor or in the core (50% of the tumor from the center) in the MC38 model 3 weeks after tumor inoculation. Treatment was same as in A. Blue, nucleus; green, CD3. (H) T cell and macrophage infiltrate histological quantification in the Hepa1.6 model 2 weeks after tumor inoculation. FI, fluorescent intensity. Treatment was same as in C. Blue, nucleus; green, CD3; red, F4/80. Original magnification, ×20. *P < 0.05, **P < 0.01 or ##P < 0.01, ***P < 0.005, ****P < 0.001, compared with control group; §§P < 0.01, §§§P < 0.005 for T cell monotherapies compared with combination, unpaired Kruskall-Wallis test, Mann-Whitney U test, or log-rank test or survival.