LTX-315 sequentially promotes lymphocyte-independent and lymphocyte-dependent antitumor effects.

IF 4.1 Q2 CELL BIOLOGY
Hsin-Wei Liao, Christopher Garris, Christina Pfirschke, Steffen Rickelt, Sean Arlauckas, Marie Siwicki, Rainer H Kohler, Ralph Weissleder, Vibeke Sundvold-Gjerstad, Baldur Sveinbjørnsson, Øystein Rekdal, Mikael J Pittet
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引用次数: 0

Abstract

LTX-315 is an oncolytic peptide that has antitumor efficacy in mice grafted with various tumor cell lines and is currently being tested in phase II clinical trials. Here we aimed to further evaluate LTX-315 in conditional genetic mouse models of cancer that typically resist current treatment options and to better understand the drug's mode of action in vivo. We report LTX-315 mediates profound antitumor effects against Braf- and Pten-driven melanoma and delays the progression of Kras- and P53-driven soft tissue sarcoma in mice. Additionally, we show in melanoma that LTX-315 triggers two sequential phases of antitumor response. The first phase of response, which begins within minutes of drug delivery into tumors, is defined by disrupted tumor vasculature and decreased tumor burden and occurs independently of lymphocytes. The second phase of response, which continues over weeks, is defined by long-term alteration of the tumor microenvironment; the changes induced by LTX-315 are most notably characterized by CD8+ T cell infiltration. We further show that these CD8+ T cells are involved in suppressing melanoma outgrowth in mice and report similar CD8+ T cell infiltration following LTX-315 treatment in melanoma and sarcoma patients. Taken together, these findings reveal LTX-315's multiple antitumor effects, including disrupting the tumor vasculature and promoting the conversion of poorly immunogenic tumors into ones that display antitumor T cell immunity.

LTX-315依次促进淋巴细胞非依赖性和淋巴细胞依赖性的抗肿瘤作用
LTX-315是一种溶瘤肽,对移植了多种肿瘤细胞系的小鼠具有抗肿瘤功效,目前正在进行II期临床试验。在这里,我们的目标是进一步评估LTX-315在条件遗传癌症小鼠模型中的作用,这些模型通常对当前的治疗方案产生抵抗,并更好地了解该药物在体内的作用模式。我们报道LTX-315对Braf和pten驱动的黑色素瘤具有深远的抗肿瘤作用,并延缓Kras和p53驱动的小鼠软组织肉瘤的进展。此外,我们发现LTX-315在黑色素瘤中触发两个连续的抗肿瘤反应阶段。第一反应阶段在药物进入肿瘤几分钟内开始,定义为肿瘤脉管系统被破坏和肿瘤负荷减少,并且独立于淋巴细胞发生。第二阶段反应持续数周,定义为肿瘤微环境的长期改变;LTX-315诱导的变化以CD8+ T细胞浸润最为显著。我们进一步证明这些CD8+ T细胞参与抑制小鼠黑色素瘤的生长,并报告了LTX-315治疗后黑色素瘤和肉瘤患者中类似的CD8+ T细胞浸润。综上所述,这些发现揭示了LTX-315的多种抗肿瘤作用,包括破坏肿瘤血管和促进免疫原性差的肿瘤转化为具有抗肿瘤T细胞免疫的肿瘤。
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来源期刊
Cell Stress
Cell Stress Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (miscellaneous)
CiteScore
13.50
自引率
0.00%
发文量
21
审稿时长
15 weeks
期刊介绍: Cell Stress is an open-access, peer-reviewed journal that is dedicated to publishing highly relevant research in the field of cellular pathology. The journal focuses on advancing our understanding of the molecular, mechanistic, phenotypic, and other critical aspects that underpin cellular dysfunction and disease. It specifically aims to foster cell biology research that is applicable to a range of significant human diseases, including neurodegenerative disorders, myopathies, mitochondriopathies, infectious diseases, cancer, and pathological aging. The scope of Cell Stress is broad, welcoming submissions that represent a spectrum of research from fundamental to translational and clinical studies. The journal is a valuable resource for scientists, educators, and policymakers worldwide, as well as for any individual with an interest in cellular pathology. It serves as a platform for the dissemination of research findings that are instrumental in the investigation, classification, diagnosis, and therapeutic management of major diseases. By being open-access, Cell Stress ensures that its content is freely available to a global audience, thereby promoting international scientific collaboration and accelerating the exchange of knowledge within the research community.
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