Mathematical modeling indicates that regulatory inhibition of CD8+ T cell cytotoxicity can limit efficacy of IL-15 immunotherapy in cases of high pre-treatment SIV viral load.
Mathematical modeling indicates that regulatory inhibition of CD8+ T cell cytotoxicity can limit efficacy of IL-15 immunotherapy in cases of high pre-treatment SIV viral load.
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DOI：
10.1371/journal.pcbi.1011425
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发表时间：
2023-08
影响因子：
4.3
通讯作者：
中科院分区：
文献类型：
--
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免疫细胞因子可以激活免疫细胞对抗癌症和慢性感染。N-803是一种IL-15超激动剂，可扩增CD 8 + T细胞并增加其细胞毒性。N-803还暂时降低了感染猴免疫缺陷病毒（SIV）（一种HIV模型）的非人灵长类动物的病毒载量。然而，尚未在所有SIV队列中观察到病毒抑制，可能取决于治疗前病毒载量和对CD 8 + T细胞的相应影响。从现有的N-803免疫治疗SIV的机理数学模型开始，我们开发了一个模型，该模型包括抗原、炎症和N-803对SIV特异性和非SIV特异性CD 8 + T细胞的激活。还包括抑制CD 8 + T细胞增殖和功能的调节性反应答，代表免疫检查点分子和免疫抑制细胞的作用。我们同时校准两个独立的SIV队列模型。第一个队列在治疗前具有低病毒载量（103 -4 log病毒RNA拷贝当量（CEQ）/mL），N-803治疗短暂抑制了病毒载量。第二个具有更高的治疗前病毒载量（105 -7 log CEQ/mL），并且使用N-803未观察到一致的病毒抑制。数学模型可以基于不同的治疗前病毒载量和由于这些病毒载量导致的不同水平的CD 8 + T细胞调节抑制（即模型的初始条件）复制两个队列的病毒和CD 8 + T细胞动力学。我们的预测得到了来自这些和其他SIV队列的额外数据的验证。虽然两个队列在模拟中具有大量的活化的SIV特异性CD 8 + T细胞，但由于细胞毒性的抑制升高，在高病毒载量队列中排除了病毒抑制。因此，我们在数学上证明了治疗前病毒载量如何影响免疫效力，突出了体内条件和联合治疗，可以最大限度地提高疗效和改善治疗结果。免疫疗法支持和重定向免疫系统以对抗慢性感染和癌症。然而，一些免疫疗法的有效性可能取决于治疗前炎症的水平以及通常用于防止免疫过度反应的调节细胞和免疫检查点分子的相应存在。在这里，我们考虑了两个先前发表的猕猴队列，这些猕猴被给予免疫球蛋白N-803来治疗猿猴免疫缺陷病毒，一种人类免疫缺陷病毒（HIV）的类似物。一个队列在治疗前病毒载量较低，N-803暂时抑制了病毒载量。第二个队列的病毒载量较高，N-803治疗后病毒载量并未持续下降。在这项工作中，我们用数学模型证明了这两种不同的结果是如何仅仅由于不同的病毒载量和相应的免疫激活和调节反应而产生的。在该模型中，我们发现关键的限制因素是免疫检查点分子对免疫细胞的细胞毒性作用的直接抑制。该模型表明，同时阻断免疫检查点分子可能是有效应用N-803治疗HIV所必需的。这种模型和类似的模型可以为癌症和慢性感染的联合治疗的设计提供信息。
Immunotherapeutic cytokines can activate immune cells against cancers and chronic infections. N-803 is an IL-15 superagonist that expands CD8+ T cells and increases their cytotoxicity. N-803 also temporarily reduced viral load in a limited subset of non-human primates infected with simian immunodeficiency virus (SIV), a model of HIV. However, viral suppression has not been observed in all SIV cohorts and may depend on pre-treatment viral load and the corresponding effects on CD8+ T cells. Starting from an existing mechanistic mathematical model of N-803 immunotherapy of SIV, we develop a model that includes activation of SIV-specific and non-SIV-specific CD8+ T cells by antigen, inflammation, and N-803. Also included is a regulatory counter-response that inhibits CD8+ T cell proliferation and function, representing the effects of immune checkpoint molecules and immunosuppressive cells. We simultaneously calibrate the model to two separate SIV cohorts. The first cohort had low viral loads prior to treatment (≈3–4 log viral RNA copy equivalents (CEQ)/mL), and N-803 treatment transiently suppressed viral load. The second had higher pre-treatment viral loads (≈5–7 log CEQ/mL) and saw no consistent virus suppression with N-803. The mathematical model can replicate the viral and CD8+ T cell dynamics of both cohorts based on different pre-treatment viral loads and different levels of regulatory inhibition of CD8+ T cells due to those viral loads (i.e. initial conditions of model). Our predictions are validated by additional data from these and other SIV cohorts. While both cohorts had high numbers of activated SIV-specific CD8+ T cells in simulations, viral suppression was precluded in the high viral load cohort due to elevated inhibition of cytotoxicity. Thus, we mathematically demonstrate how the pre-treatment viral load can influence immunotherapeutic efficacy, highlighting the in vivo conditions and combination therapies that could maximize efficacy and improve treatment outcomes. Immunotherapy bolsters and redirects the immune system to fight chronic infections and cancers. However, the effectiveness of some immunotherapies may depend on the level of pre-treatment inflammation and the corresponding presence of regulatory cells and immune checkpoint molecules that normally function to prevent immune overreaction. Here, we consider two previously published cohorts of macaques who were given the immunotherapeutic N-803 to treat Simian Immunodeficiency Virus, an analog of Human Immunodeficiency Virus (HIV). One cohort had low viral loads before treatment, and N-803 temporarily suppressed viral loads. The second cohort had high viral loads that did not consistently decrease with N-803 treatment. In this work, we demonstrate with a mathematical model how these two distinct outcomes can arise due only to the different viral loads and the corresponding immune activation and regulatory response. In the model, we find that the key limiting factor is the direct inhibition of the cytotoxic action of immune cells by immune checkpoint molecules. This model indicates that simultaneous blockade of immune checkpoint molecules may be necessary for effective application of N-803 for the treatment of HIV. This and similar models can inform the design of such combination therapies for cancer and chronic infection.
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影响因子：
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