T cell Biology Program, Centenary Institute of Cancer Medicine and Cell Biology, Sydney, NSW, Australia.
Pillai Labratory, Ragon Institute of MGH, Harvard and MIT, Boston, MA, USA.
Oncoimmunology. 2023 Dec 10;13(1):2290799. doi: 10.1080/2162402X.2023.2290799. eCollection 2024.
There has been growing interest in the role of B cells in antitumour immunity and potential use in adoptive cellular therapies. To date, the success of such therapies is limited. The intrinsic capacity of B cells to specifically activate tumour-specific CD4+ T cells via TCR-dependent interactions remains poorly defined. We have developed an tumour model that utilizes MHCII I-E restriction which limits antigen presentation to tumour-specific CD4 T cells to either tumour-specific B cells or host myeloid antigen presenting cells (APCs) in lymphopenic RAG-/-mice. We have previously shown that these naive tumour-specific CD4+ T cells can successfully eradicate established tumours in this model when activated by host APCs. When naïve tumour-specific B cells are the only source of I-E+ APC, very limited proliferation of naïve CD4+ T cells is observed, whereas host I-E+ APCs are potent T cell activators. B cells pre-activated with an anti-CD40 agonistic antibody support increased T cell proliferation, although far less than host APCs. CD4+ T cells that have already differentiated to an effector/central memory phenotype proliferate more readily in response to naïve B cells, although still 100-fold less than in response to host APCs. This study demonstrates that even in a significantly lymphopenic environment, myeloid APCs are the dominant primary activators of tumour-specific T cells, in contrast to the very limited capacity of tumour-specific B cells. This suggests that future anti-tumour therapies that incorporate activated B cells should also include mechanisms that activate host APCs.
人们对 B 细胞在抗肿瘤免疫中的作用以及在过继细胞疗法中的潜在应用越来越感兴趣。迄今为止，此类疗法的成功有限。B 细胞通过 TCR 依赖性相互作用特异性激活肿瘤特异性 CD4+T 细胞的内在能力仍未得到充分定义。我们开发了一种利用 MHCII I-E 限制的肿瘤模型，该限制将抗原呈递给淋巴减少的 RAG-/-小鼠中肿瘤特异性 CD4 T 细胞的能力仅限于肿瘤特异性 B 细胞或宿主髓样抗原呈递细胞 (APC)。我们之前曾表明，当这些幼稚的肿瘤特异性 CD4+T 细胞被宿主 APC 激活时，它们可以成功清除该模型中的已建立肿瘤。当幼稚的肿瘤特异性 B 细胞是唯一的 I-E+APC 来源时，观察到幼稚 CD4+T 细胞的增殖非常有限，而宿主 I-E+APC 是有效的 T 细胞激活物。用抗 CD40 激动性抗体预先激活的 B 细胞支持增加的 T 细胞增殖，尽管远不及宿主 APC。已经分化为效应/中央记忆表型的 CD4+T 细胞更容易对幼稚 B 细胞增殖，尽管仍比对宿主 APC 的反应低 100 倍。这项研究表明，即使在明显的淋巴减少环境中，髓样 APC 也是肿瘤特异性 T 细胞的主要初始激活物，而肿瘤特异性 B 细胞的能力非常有限。这表明，未来包含激活 B 细胞的抗肿瘤疗法还应包括激活宿主 APC 的机制。
