PO.CL05.05 · 临床研究

Identifying cancer cell intrinsic regulators of radiation-induced interferon signaling

编号 2559 展板 3 时间 4/20 09:00–12:00 区域 Section 45 主讲 Olivia Kaneko, BS

分会场 Immunomodulatory Effects of Targeted Therapies

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作者与单位

Olivia Kaneko¹, Bon Ham Yip¹, Arnav Mehta², Nir Hacohen², Ryan J. Park¹

¹Experimental Radiation Oncology, MD Anderson Cancer Center, Houston, TX,²Broad Institute, Cambridge, MA and Massachusetts General Hospital, Charlestown, MA, Charlestown, MA

摘要 Abstract

Induction of anti-tumor immunity by radiation therapy (RT) has been observed in multiple preclinical models and in selected patients and can lead to durable systemic tumor regression. Modulation of anti-tumor immunity by RT is thought to act primarily via cGAS-STING activation leading to type I interferon (IFN) response pathways, which coordinate T cell priming and recruitment and adaptive resistance such as PD-L1 induction. Individual studies have demonstrated both immune activating and immune suppressive effects of RT in various contexts, and the determinants of this wide variability are poorly understood. Discovering divergent and convergent mechanisms of type I IFN response to RT across diverse cancer cell states may thus define biomarkers and treatment strategies to enhance RT-driven immune activation. We treated 100 human cancer cell lines with 2 Gy or 8 Gy RT or the STING agonist DiABZI and performed single cell RNA sequencing. We scored cell lines using a composite of IFN response genes as well as individual IFN response genes including ISG15, MX1, CXCL10 and IFNB. We then selected four cell lines with high radiation-induced IFN response for mechanistic studies: two derived from pancreatic ductal adenocarcinoma and two from breast carcinoma. We observed distinct kinetics of ISG15 and MX1 activation between 2 Gy and 8 Gy RT and DiABZI as well as between cell lines. Notably, knockout of STING abrogated DiABZI response but paradoxically increased ISG15 induction by radiation in MDA-MB-231, but not SUIT-2. Our study highlights wide variability among cancer cell states in modulation of IFN response signatures by radiation and emphasizes the need to elucidate mechanisms of radiation-induced immune activation and suppression across diverse cancer types.

利益披露 Disclosure

O. Kaneko, None.. B. Yip, None. A. Mehta, Plexium g., Board of Directors, non-salaried role). SyntheX g., Board of Directors, non-salaried role). Monimoi g., Board of Directors, non-salaried role), Stock. Juri Biosciences g., Board of Directors, non-salaried role). CxT Discovery g., Board of Directors, non-salaried role). Third Rock Ventures g., Board of Directors, non-salaried role). Asher Biotherapeutics g., Board of Directors, non-salaried role), Stock. Abata Therapeutics g., Board of Directors, non-salaried role), Stock. Clasp Therapeutics g., Board of Directors, non-salaried role), Stock. Flare Therapeutics g., Board of Directors, non-salaried role). venBio Partners g., Board of Directors, non-salaried role). BioNTech g., Board of Directors, non-salaried role). Rheos Medicines g., Board of Directors, non-salaried role). Checkmate Pharmaceuticals g., Board of Directors, non-salaried role). The Column Group Other Business Ownership, Venture Partner. Monet Lab Stock. Bristol-Myers Squibb ). N. Hacohen, Danger Bio/Related Sciences g., Board of Directors, non-salaried role), Stock. Repertoire Immune Medicines g., Board of Directors, non-salaried role). CytoReason g., Board of Directors, non-salaried role). BioNTech Stock, Patent. Bristol-Myers Squibb ). Moderna ). JJDC ). Takeda ). Calico Life Sciences ). R. J. Park, None.

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