Department of Human & Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298.
Department of Biochemistry, Virginia Commonwealth University School of Medicine, Richmond, VA 23298.
Proc Natl Acad Sci U S A. 2023 Sep 26;120(39):e2302878120. doi: 10.1073/pnas.2302878120. Epub 2023 Sep 18.
Although tumor-intrinsic fatty acid β-oxidation (FAO) is implicated in multiple aspects of tumorigenesis and progression, the impact of this metabolic pathway on cancer cell susceptibility to immunotherapy remains unknown. Here, we report that cytotoxicity of killer T cells induces activation of FAO and upregulation of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme of FAO in cancer cells. The repression of CPT1A activity or expression renders cancer cells more susceptible to destruction by cytotoxic T lymphocytes. Our mechanistic studies reveal that FAO deficiency abrogates the prosurvival signaling in cancer cells under immune cytolytic stress. Furthermore, we identify T cell-derived IFN-γ as a major factor responsible for induction of CPT1A and FAO in an AMPK-dependent manner, indicating a dynamic interplay between immune effector cells and tumor targets. While cancer growth in the absence of CPT1A remains largely unaffected, established tumors upon FAO inhibition become significantly more responsive to cellular immunotherapies including chimeric antigen receptor-engineered human T cells. Together, these findings uncover a mode of cancer resistance and immune editing that can facilitate immune escape and limit the benefits of immunotherapies.
虽然肿瘤内在的脂肪酸β氧化（FAO）与肿瘤发生和进展的多个方面有关，但该代谢途径对癌细胞对免疫疗法的敏感性的影响尚不清楚。在这里，我们报告称，杀伤性 T 细胞的细胞毒性诱导 FAO 的激活和肉毒碱棕榈酰转移酶 1A（CPT1A）的上调，CPT1A 是 FAO 在癌细胞中的限速酶。CPT1A 活性或表达的抑制使癌细胞更容易被细胞毒性 T 淋巴细胞破坏。我们的机制研究表明，FAO 缺乏会破坏免疫细胞毒性应激下癌细胞中的存活信号。此外，我们确定 T 细胞衍生的 IFN-γ是 CPT1A 和 FAO 诱导的主要因素，以 AMPK 依赖的方式，表明免疫效应细胞和肿瘤靶标之间存在动态相互作用。虽然缺乏 CPT1A 的癌症生长仍然在很大程度上不受影响，但在 FAO 抑制下建立的肿瘤对细胞免疫疗法（包括嵌合抗原受体工程化的人 T 细胞）变得更加敏感。总之，这些发现揭示了一种癌症抵抗和免疫编辑的模式，这种模式可以促进免疫逃逸并限制免疫疗法的益处。
