American Association for Cancer Research
Browse
10780432ccr171365-sup-183215_3_supp_4512653_p2pxcs.docx (1.79 MB)

Supplement Figures S1-S4 from T-cell Homing Therapy for Reducing Regulatory T Cells and Preserving Effector T-cell Function in Large Solid Tumors

Download (1.79 MB)
journal contribution
posted on 2023-03-31, 19:45 authored by Jiemiao Hu, Chuang Sun, Chantale Bernatchez, Xueqing Xia, Patrick Hwu, Gianpietro Dotti, Shulin Li

Fig. S1. CD4+ T cell infiltration in mouse and human tumor sections. Fig. S2. Correlations between the numbers of infiltrated murine T cells and the ratios of costimulatory and coinhibitory receptors. Fig. S3. Quantitative PCR analysis of CXCL9 and CXCL10 mRNA expression in tumor cells that were treated with doxorubicin. Fig. S4. Induction of CXCL9 and CXCL10 at mRNA levels in LLC and Mel2549 tumors after the treatment with IL-12 plus doxorubicin plus T cell infusion.

Funding

NIH

University of Texas MD Anderson's Genetically Engineered Mouse Facility

History

ARTICLE ABSTRACT

Purpose: Infused autologous tumor-infiltrating lymphocytes (TIL) and tumor-targeted chimeric antigen receptor (CAR) T cells typically surround malignant lesions or penetrate small tumor nodules but fail to penetrate large solid tumors, significantly compromising their antitumor impact. Strategies to overcome this primary challenge are largely required.Experimental Design: We tested the effects of IL12 plus doxorubicin on T-cell penetration and efficacy in solid tumors in a murine lung cancer model, a murine breast carcinoma lung metastasis model, and two human xenograft tumor models bearing large tumors (>10 mm).Results: Intriguingly, this simple approach increased the numbers, the distribution, and the depth of penetration of infused CD8+ T cells in these tumors, including both TILs and CAR T cells. This combined treatment halted tumor progression and significantly extended survival time. Studies of the underlying mechanism revealed multiple effects. First, the combined treatment maintained the high ratios of immune-stimulatory receptors to immune-inhibitory receptors on infiltrated CD8+ T cells, reduced the accumulation of immunosuppressive regulatory T cells, and enhanced the numbers of T-bet+ effector T cells in the tumors. Second, doxorubicin induced chemokines CXCL9 and CXCL10, which may attract NKG2D+CD8+ T cells to tumors, and this effect was boosted by IL12-induced IFNγ accumulation in tumors, promoting the penetration of NKG2D+CD8+ T cells.Conclusions: The deep penetration of infused T cells associated with combined IL12 plus doxorubicin yielded striking therapeutic effects in murine and human xenograft solid tumors. This approach might broaden the application of T-cell therapy to a wider range of solid tumors. Clin Cancer Res; 24(12); 2920–34. ©2018 AACR.See related commentary by Berraondo et al., p. 2716