Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, United States.
Department of Pediatrics, Division of Hematology and Oncology, University of Washington, Seattle, WA, United States.
Front Immunol. 2021 Nov 11;12:706150. doi: 10.3389/fimmu.2021.706150. eCollection 2021.
Robust T cell responses are crucial for effective anti-tumor responses and often dictate patient survival. However, in the context of solid tumors, both endogenous T cell responses and current adoptive T cell therapies are impeded by the immunosuppressive tumor microenvironment (TME). A multitude of inhibitory signals, suppressive immune cells, metabolites, hypoxic conditions and limiting nutrients are believed to render the TME non-conducive to sustaining productive T cell responses. In this study we conducted an in-depth phenotypic and functional comparison of tumor-specific T cells and tumor-nonspecific bystander memory T cells within the same TME. Using two distinct TCR transgenic and solid-tumor models, our data demonstrate that despite exposure to the same cell-extrinsic factors of the TME, the tumor-nonspecific bystander CD8 T cells retain the complete panoply of memory markers, and do not share the same exhaustive phenotype as tumor-reactive T cells. Compared to tumor-specific T cells, bystander memory CD8 T cells in the TME also retain functional effector cytokine production capabilities in response to cognate antigenic stimulation. Consistent with these results, bystander memory T cells isolated from tumors showed enhanced recall responses to secondary bacterial challenge in a T cell transplant model. Importantly, the tumor-resident bystander memory cells could also efficiently utilize the available resources within the TME to elaborate recall effector functions following intra-tumoral peptide antigen injection. Additionally, CRISPR-Cas9 gene deletion studies showed that CXCR3 was critical for the trafficking of both tumor antigen-specific and bystander memory T cells to solid tumors. Collectively, these findings that T cells can persist and retain their functionality in distinct solid tumor environments in the absence of cognate antigenic stimulation, support the notion that persistent antigenic signaling is the central driver of T cell exhaustion within the TME. These studies bear implications for programming more efficacious TCR- and CAR-T cells with augmented therapeutic efficacy and longevity through regulation of antigen and chemokine receptors.
强大的 T 细胞反应对于有效的抗肿瘤反应至关重要，通常决定着患者的生存。然而，在实体瘤的背景下，内源性 T 细胞反应和当前的过继性 T 细胞疗法都受到免疫抑制性肿瘤微环境 (TME)的阻碍。许多抑制性信号、抑制性免疫细胞、代谢物、缺氧条件和有限的营养物质被认为使 TME 不利于维持有效的 T 细胞反应。在这项研究中，我们对同一 TME 内的肿瘤特异性 T 细胞和肿瘤非特异性旁观者记忆 T 细胞进行了深入的表型和功能比较。使用两种不同的 TCR 转基因和实体瘤模型，我们的数据表明，尽管暴露于 TME 的相同细胞外在因素下，肿瘤非特异性旁观者 CD8 T 细胞保留了完整的记忆标志物谱，并且与肿瘤反应性 T 细胞没有相同的耗尽表型。与肿瘤特异性 T 细胞相比，TME 中的旁观者记忆 CD8 T 细胞在对同源抗原刺激时也保留了功能性效应细胞因子产生的能力。与这些结果一致，从肿瘤中分离出的旁观者记忆 T 细胞在 T 细胞移植模型中对二次细菌挑战表现出增强的回忆反应。重要的是，肿瘤驻留的旁观者记忆细胞也可以有效地利用 TME 中的可用资源，在肿瘤内注射肽抗原后发挥回忆效应功能。此外，CRISPR-Cas9 基因缺失研究表明，CXCR3 对于肿瘤抗原特异性和旁观者记忆 T 细胞向实体瘤的迁移都是至关重要的。总之，这些发现表明，在没有同源抗原刺激的情况下，T 细胞可以在不同的实体瘤环境中持续存在并保持其功能，这支持了持续的抗原信号是 TME 中 T 细胞耗竭的核心驱动因素的观点。这些研究对于通过调节抗原和趋化因子受体来编程更有效的 TCR-和 CAR-T 细胞以提高治疗效果和持久性具有重要意义。
