Busselaar Julia, Sijbranda Merel, Borst Jannie
Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
Immunol Lett. 2024 Dec;270:106938. doi: 10.1016/j.imlet.2024.106938. Epub 2024 Oct 28.
Both type I interferon (IFN-I) and CD4 T-cell help are required to generate effective CD8 T-cell responses to cancer. We here outline based on existing literature how IFN-I signaling and CD4 T-cell help are connected. Both impact on the functional state of dendritic cells (DCs), particularly conventional (c)DC1. The cDC1s are critical for crosspresentation of cell-associated antigens and for delivery of CD4 T-cell help for cytotoxic T-lymphocyte (CTL) effector and memory differentiation. In infection, production of IFN-I is prompted by pathogen-associated molecular patterns (PAMPs), while in cancer it relies on danger-associated molecular patterns (DAMPs). IFN-I production by tumor cells and pDCs in the tumor micro-environment (TME) is often limited. IFN-I signals increase the ability of migratory cDC1s and cDC2s to transport tumor antigens to tumor-draining lymph nodes (tdLNs). IFN-I also enables cDC1s to form and sustain the platform for help delivery by stimulating the production of chemokines that attract CD4 and CD8 T cells. IFN-I promotes delivery of help in concert with CD40 signals by additive and synergistic impact on cross-presentation and provision of critical costimulatory and cytokine signals for CTL effector and memory differentiation. The scenario of CD4 T-cell help therefore depends on IFN-I signaling. This scenario can play out in tdLNs as well as in the TME, thereby contributing to the cancer immunity cycle. The collective observations may explain why both IFN-I and CD4 T-cell help signatures in the TME correlate with good prognosis and response to PD-1 targeting immunotherapy in human cancer. They also may explain why a variety of tumor types in which IFN-I signaling is attenuated, remain devoid of functional CTLs.
产生有效的针对癌症的CD8 T细胞反应既需要I型干扰素（IFN-I），也需要CD4 T细胞的辅助。我们在此根据现有文献概述IFN-I信号传导与CD4 T细胞辅助是如何联系的。二者均影响树突状细胞（DC）的功能状态，尤其是常规（c）DC1。cDC1对于细胞相关抗原的交叉呈递以及为细胞毒性T淋巴细胞（CTL）效应器和记忆分化提供CD4 T细胞辅助至关重要。在感染中，病原体相关分子模式（PAMP）促使IFN-I产生，而在癌症中，它依赖于危险相关分子模式（DAMP）。肿瘤微环境（TME）中的肿瘤细胞和浆细胞样DC（pDC）产生的IFN-I通常有限。IFN-I信号增强迁移性cDC1和cDC2将肿瘤抗原转运至肿瘤引流淋巴结（tdLN）的能力。IFN-I还通过刺激吸引CD4和CD8 T细胞的趋化因子产生，使cDC1能够形成并维持辅助传递平台。IFN-I通过对交叉呈递产生累加和协同作用，并为CTL效应器和记忆分化提供关键的共刺激和细胞因子信号，与CD40信号协同促进辅助传递。因此，CD4 T细胞辅助的情况取决于IFN-I信号传导。这种情况可在tdLN以及TME中发生，从而促进癌症免疫循环。这些总体观察结果可能解释了为什么TME中的IFN-I和CD4 T细胞辅助特征均与人类癌症中良好的预后以及对PD-1靶向免疫疗法的反应相关。它们还可能解释了为什么多种IFN-I信号传导减弱的肿瘤类型仍然缺乏功能性CTL。
