Journal: Cancer Communications

Article Title: CD24 is a promising immunotherapeutic target for enhancing efficacy of third‐generation EGFR‐TKIs on EGFR‐mutated lung cancer

doi: 10.1002/cac2.70068

Figure Lengend Snippet: Knockout of CD24 or using ATG‐031 (anti‐CD24 antibody) synergized with third‐generation EGFR‐TKIs to enhance cancer clearance in CDXs, spontaneous lung cancer, and PDX murine models . (A‐B) Schematic description of establishment and treatment line of PC‐9 CDXs. For macrophage depletion, 150 µL liposomal clodronate or control liposomes were injected intravenously via the retro‐orbital sinus 2 days prior to tumor engraftment, and subsequent maintenance doses of 100 µL liposomal clodronate or control liposomes were injected every 3 days throughout the duration of the experiment. (C‐D) Representative images and analysis of tumor response to osimertinib among xenografts harboring PC‐9 WT or ΔCD24 cells, or PC‐9 WT cells treated with IgG1, ATG‐031, or ATG‐031 combined with macrophage depletion ( n = 9 for each group). Knockout of CD24 or anti‐CD24 therapy with ATG‐031 resulted in heightened anti‐tumor effect of osimertinib on PC‐9 xenografts. (E) Schematic description of human EGFR L858R/T790M ‐driven spontaneous lung tumor mice model expressing humanized CD24 using the Cre‐LoxP technology. (F‐G) Survival analysis and representative images of chest computed tomography displaying tumor response to treatments in mice bearing EGFR L858R/T790M ‐driven spontaneous lung tumor expressing humanized CD24 ( n = 6 for each group). The combination therapy of osimertinib and ATG‐031 antibody exhibited a greater anti‐tumor effect and a significant survival advantage compared to osimertinib monotherapy. (H) Schematic description of 3 PDX models with residual EGFR‐mutated lung tumors after osimertinib treatment before surgery. Macrophages were depleted with 400 µg αCSF1R three times per week for 18 days before tumor engraftment in the third generation of the mice, and throughout the duration of the experiment. (I‐J) Comparison of PDX volume changes in mice with TAMs or in TAM‐depleted mice treated with IgG1, ATG‐031, osimertinib or their combination therapies. The combination therapy of osimertinib and ATG‐031 antibody exhibited synergistic effect on tumor reduction and TAM depletion abrogated the reduction. Sidak's multiple comparisons tests were applied for (D). Log‐rank test was applied for (F). Tukey's multiple comparisons tests were applied for (D). P < 0.05 was defined as statistically significant. Abbreviations: CDX, Cell‐derived xenograft; PDX, patient's tumor‐derived xenograft; TAM, tumor associated‐macrophage.

Article Snippet: For macrophage depletion, 150 μL liposomal clodronate (MedChemExpress), or control liposomes (MedChemExpress) were injected intravenously via the retro‐orbital sinus 2 days prior to tumor engraftment, and subsequent maintenance doses of 100 μL liposomal clodronate (MedChemExpress) or control liposomes (MedChemExpress) were injected every 3 days throughout the duration of the experiment.

Techniques: Knock-Out, Control, Liposomes, Injection, Expressing, Computed Tomography, Comparison, Derivative Assay