| Autor: |
Jagodinsky, Justin C., Vera, Jessica M., Jin, Won Jong, Shea, Amanda G., Clark, Paul A., Sriramaneni, Raghava N., Havighurst, Thomas C., Chakravarthy, Ishan, Allawi, Raad H., Kim, KyungMann, Harari, Paul M., Sondel, Paul M., Newton, Michael A., Crittenden, Marka R., Gough, Michael J., Miller, Jessica R., Ong, Irene M., Morris, Zachary S. |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 9/18/2024, Vol. 16 Issue 765, p1-21, 21p |
| Abstrakt: |
Radiation therapy (RT) activates multiple immunologic effects in the tumor microenvironment (TME), with diverse dose-response relationships observed. We hypothesized that, in contrast with homogeneous RT, a heterogeneous RT dose would simultaneously optimize activation of multiple immunogenic effects in a single TME, resulting in a more effective antitumor immune response. Using high-dose-rate brachytherapy, we treated mice bearing syngeneic tumors with a single fraction of heterogeneous RT at a dose ranging from 2 to 30 gray. When combined with dual immune checkpoint inhibition in murine models, heterogeneous RT generated more potent antitumor responses in distant, nonirradiated tumors compared with any homogeneous dose. The antitumor effect after heterogeneous RT required CD4 and CD8 T cells and low-dose RT to a portion of the tumor. At the 3-day post-RT time point, dose heterogeneity imprinted the targeted TME with spatial differences in immune-related gene expression, antigen presentation, and susceptibility of tumor cells to immune-mediated destruction. At a later 10-day post-RT time point, high-, moderate-, or low-RT-dose regions demonstrated distinct infiltrating immune cell populations. This was associated with an increase in the expression of effector-associated cytokines in circulating CD8 T cells. Consistent with enhanced adaptive immune priming, heterogeneous RT promoted clonal expansion of effector CD8 T cells. These findings illuminate the breadth of dose-dependent effects of RT on the TME and the capacity of heterogeneous RT to promote antitumor immunity when combined with immune checkpoint inhibitors. Editor's summary: Radiation therapy (RT) is usually administered as a single dose across a tumor. However, not all radiation doses are created equal. High radiation doses promote immunogenic cell death, medium radiation doses promote type I interferon responses, and low radiation doses promote inflammatory cytokine production and immune cell trafficking. To reap the benefits of all three doses, Jagodinsky et al. treated murine tumors with heterogeneous RT, where different regions of the tumor were treated with different RT doses. The authors found that this heterogeneous approach outperformed homogeneous dose RT in a T cell–dependent manner and could be combined with immune checkpoint inhibition. These data support further clinical development of heterogeneous RT. —Courtney Malo [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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