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Intrinsic tumor resistance to CAR T-cells is a dynamic transcriptional state that can be exploited with low dose radiation

ABSTRACT: Purpose: High tumor burden prior to CAR T-cell therapy predicts poor outcome, however it is unclear if this is driven more by cell number or underlying biology. It is also unclear if tumor intrinsic properties that confer CAR T-cell resistance can be clinically manipulated to improve response. Here we capitalize on radiation’fering effects by dose in vivo to examine the relative importance of tumor quantity versus quality prior to CAR T-cell therapy. Experimental Design: Using Nalm6 ALL tumor-bearing mice, we investigate the impact of high dose (20Gy in 5 fractions) radiation to focal bulky disease, versus less cytotoxic low-dose (1.8Gy) to all disease (total tumor irradiation; TTI) on CAR T-cell efficacy. We characterize the dynamics of predictive transcriptional states in mice and patients using tumor RNA-seq under conditions of excellent vs poor response. Results: We find the in vivo sensitivity of leukemia cells to CAR T-cells is not only predicted by a transcriptional score, but this score can be temporarily increased by low dose TTI, which is associated with significantly improved survival. Focal high dose radiation (as is currently done clinically) was more debulking but did not improve survival. The tumor transcriptional state induced by low dose radiation was found in >80% of long-term CAR T-cell survivors. Conclusions: These findings provide a path to 1) identify patients unlikely to respond to CAR T_x0002_cells due to potentially reversible tumor-intrinsic resistance, and 2) potentially improve response using low dose TTI to adjust a tumor’s unfavorable transcriptional state prior to CAR T-cell delivery.

ORGANISM(S): Homo sapiens

PROVIDER: GSE225020 | GEO | 2023/09/27

REPOSITORIES: GEO

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Project description:This is a genome-wide approach to identifying genes persistently induced in the mouse mammary gland by acute whole body low dose ionizing radiation (10cGy), 1 and 4 weeks after exposure. Gene expression that is modified under these parameters were compared between Tgfb1 wild type and heterozygote littermates in order to determine which genes induced or repressed by radiation were mediated via Tgfb1 status. Differential gene expression was analyzed in Tgfb1 heterozygote and wild type littermate 4th mammary glands, after whole body exposure to an acute dose of 10cGy ionizing radiation. Estrus cycle was normalized in all mice two days prior to irradiation by injection with an estrogen and progesterone mixture. It is widely believed that the carcinogenic action of ionizing radiation is due to targeted DNA damage and resulting mutations, but there is also substantial evidence that non-targeted radiation effects alter epithelial phenotype and the stromal microenvironment. Activation of transforming growth factor beta 1 (TGFbeta) is a non-targeted radiation effect that mediates cell fate decisions following DNA damage and regulates microenvironment composition; it could either suppress or promote cancer. Gene expression profiling shown herein demonstrates that low dose radiation (10 cGy) elicits persistent changes in Tgfb1 wild type and heterozygote murine mammary gland that are highly modulated by TGFbeta. We asked if such non-targeted radiation effects contribute to carcinogenesis by using a novel radiation chimera model. Unirradiated Trp53 null mammary epithelium was transplanted to the mammary stroma of mice previously exposed to a single low (10 -100 cGy) radiation dose. By 300 days, 100% of transplants in irradiated hosts at either 10 or 100 cGy had developed Trp53 null breast carcinomas compared to 54% in unirradiated hosts. Tumor growth rate was also increased by high, but not low, dose host irradiation. In contrast, irradiation of Tgfb1 heterozygote mice prior to transplantation failed to decrease tumor latency, or increase growth rate at any dose. Host irradiation significantly reduced the latency of invasive ductal carcinoma compared to spindle cell carcinoma, as well as those tumors negative for smooth muscle actin in wild type but not Tgfb1 heterozygote mice. However, irradiation of either host genotype significantly increased the frequency of estrogen receptor negative tumors. These data demonstrate two concepts critical to understanding radiation risks. First, non-targeted radiation effects can significantly promote the frequency and alter the features of epithelial cancer. Second, radiation-induced TGFbeta activity is a key mechanism of tumor promotion. Keywords: Differential gene expression after low dose irradiation Two genotypes: TGBbeta1 heterozygote and wildtype mouse mammary glands. Two time points post-10cGy-irradiation per genotype (1 week, 4 weeks); control time point was 1 week post-sham-irradiation. Two or three replicates per time point.

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Intrinsic tumor resistance to CAR T-cells is a dynamic transcriptional state that can be exploited with low dose radiation

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