探討虛擬記憶型CD8+ T細胞的抗腫瘤功能性

Abstract

虛擬記憶型T細胞（Virtual memory CD8+ T cells, TVM）是一群與傳統記憶型T細胞（Conventional memory T cells, TMEM）不同的CD8+ T細胞亞型。TVM細胞雖然未曾經歷過抗原刺激，卻可以表現出記憶型標誌，TVM細胞的細胞表面抗原表現為CD44hi CD62Lhi CXCR3hi CD49dlo CD122hi。作為類先天性記憶型T細胞（Innate-like memory T cells），TVM細胞可以透過對細胞激素（而非專一性抗原）的快速反應，提供對細菌或病毒感染的廣泛保護，並比初始型T細胞（Naïve T cells, TN）更快產生細胞激素，如干擾素-γ（Interferon γ, IFN-γ）。目前大多數的研究聚焦於TVM細胞在感染性疾病中的角色，然而其在腫瘤環境中的角色尚未被充分了解。 近期研究顯示，旁觀者T細胞（bystander T cells）在腫瘤中相當豐富，並且主要受到CXCL9吸引浸潤到腫瘤環境中。由於TVM細胞高度表現其受體CXCR3，我推測TVM細胞也會因此浸潤到腫瘤環境中。我使用了兩種腫瘤模型─E.G7-ova淋巴瘤模型及MC38-ova大腸直腸癌模型，兩種腫瘤細胞均會表現卵清蛋白（ovalbumin）─來進一步分析TVM細胞在脾臟、腫瘤引流淋巴結（tumor-draining lymph node, tdLN）與腫瘤浸潤性淋巴球（tumor-infiltrating lymphocytes, TILs）中的比例。結果顯示，TVM細胞可浸潤到腫瘤中，並佔CD8+ T細胞相當大的比例。在帶有MC38腫瘤的OT-I小鼠中可以發現不具有腫瘤特異性的TVM細胞依然可以浸潤到腫瘤中。TVM細胞在腫瘤中所表現的功能與其在脾臟、腫瘤引流淋巴結中有所不同，且具功能之TVM細胞比例與細胞數是與腫瘤中的TMEM細胞相當的。此外，在體外毒殺實驗中，無論是否為抗原特異性目標細胞，TVM細胞皆可展現出較TN細胞強的毒殺能力。雖然TVM可能作為腫瘤環境中的旁觀者細胞，它們仍像傳統記憶型T細胞一樣無可避免地走向耗竭的命運。但若是作為絕對旁觀者細胞的情況下，仍較傳統記憶型T細胞不易走向耗竭。 本研究指出TVM細胞可能參與抗腫瘤免疫反應，未來仍需進一步驗證TVM細胞在體內抗腫瘤免疫反應的貢獻。

Virtual memory CD8+ T cells (TVM) are a subset of CD8+ T cells distinct from conventional memory T cells (TMEM). They exhibit memory markers without prior cognate antigen exposure and are defined as CD44hi CD62Lhi CXCR3hi CD49dlo CD122hi. As innate-like memory T cells, TVM provides broad protection against bacterial and viral infections through rapid responses to cytokines rather than to cognate antigens, producing effector cytokines faster than naïve T cells (TN). While most studies have focused on their roles in infectious diseases, the involvement of TVM in tumors remains poorly understood. Recent studies have shown that bystander T cells are abundant in tumors, predominantly recruited by CXCL9. Given that TVM expresses high levels of CXCR3, the receptor for CXCL9, I hypothesize that TVM can infiltrate tumors. I investigated their presence in the spleen, tumor-draining lymph node (tdLN), and tumor-infiltrating lymphocytes (TILs) in two different tumor models: the E.G7-ova lymphoma model and the MC38-ova colorectal carcinoma, both of which express ovalbumin. Results revealed that TVM cells infiltrated tumors and constituted a substantial proportion of CD8+ T cells in both tumor models. Notably, TVM infiltration was observed even in the absence of tumor antigen-specificity, as evidenced by OT-I mice bearing MC38 tumors. Tumor-infiltrating TVM exhibited unique expression of markers distinct from those in the spleen and tdLN, and the percentages and cell numbers of functional tumor-infiltrating TVM were comparable to those of tumor-infiltrating TMEM cells. In addition, in flow cytometry-based in vitro killing assays, TVM cells showed stronger killing capacity than TN cells in both antigen-specific and bystander scenarios. TVM may be the bystander cells in the tumor microenvironments; however, they inevitably undergo exhaustion like TMEM. Interestingly, TVM showed a less exhausted phenotype in the purely bystander scenario. This study highlights the potential role of TVM cells in tumor immunity. Further investigation is warranted to validate the contribution of TVM in anti-tumor immunity in vivo.