Division of Gene and Immune Medicine, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan; Department of Pediatrics, Fukui University School of Medicine, 23-3 Shimoaizuki, Matsuoka, Yoshida-gun, Fukui, 910-1193, Japan.
Cancer Med. 2013 Oct;2(5):636-45. doi: 10.1002/cam4.117. Epub 2013 Sep 10.
Lymphopenia-induced homeostatic proliferation (HP) of T cells following autologous hematopoietic stem cell transplantation (HSCT) skews the T-cell repertoire by engaging tumor-associated antigens (TAAs), leading to an induction of antitumor immunity. Here, as the tumor-reactive lymphocytes preferentially proliferate during the condition of HP, we examined whether the priming of a donor lymphocytes to TAAs could enhance HP-induced antitumor immunity in autologous HSCT recipients. First, to examine whether the tumor-bearing condition of donor influences the antitumor effect of HSCT, the lymphocytes isolated from CT26 tumor-bearing mice were infused into lethally irradiated mice. The growth of tumors was substantially suppressed in the mice that received HSCT from a tumor-bearing donor compared with a naïve donor, suggesting that a fraction of donor lymphocytes from tumor-bearing mice are primed in response to TAAs and remain responsive upon transplantation. We previously reported that type I interferon (IFN) maturates the dendritic cells and promotes the priming of T cells. We then investigated whether the further priming of donor cells by IFN-α can strengthen the antitumor effect of HSCT. The intratumoral IFN-α gene transfer significantly increased the number of IFN-γ-positive lymphocytes in response to CT26 cells but not the syngeneic lymphocytes in donor mice. The infusion of primed donor lymphocytes markedly suppressed the tumor growth in recipient mice, and cured 64% of the treated mice. Autologous HSCT with the infusion of primed donor lymphocytes is a promising strategy to induce an effective antitumor immunity for solid cancers.
自体造血干细胞移植（HSCT）后，淋巴细胞减少诱导的 T 细胞固有增殖（HP）通过与肿瘤相关抗原（TAA）结合，使 T 细胞 repertoire 发生偏倚，从而诱导抗肿瘤免疫。在这里，由于肿瘤反应性淋巴细胞在 HP 条件下优先增殖，我们研究了供体淋巴细胞对 TAA 的初始免疫是否可以增强自体 HSCT 受者中 HP 诱导的抗肿瘤免疫。首先，为了研究供体的肿瘤状态是否影响 HSCT 的抗肿瘤作用，将来自 CT26 荷瘤小鼠的淋巴细胞输注到致死性辐照小鼠中。与来自 naive 供体的小鼠相比，接受来自荷瘤供体 HSCT 的小鼠的肿瘤生长明显受到抑制，这表明来自荷瘤小鼠的供体淋巴细胞的一部分已针对 TAA 进行了初始免疫，并且在移植后仍具有反应性。我们之前报道过，I 型干扰素（IFN）使树突状细胞成熟并促进 T 细胞的初始免疫。然后，我们研究了 IFN-α 对供体细胞的进一步初始免疫是否可以增强 HSCT 的抗肿瘤作用。肿瘤内 IFN-α 基因转移显著增加了对 CT26 细胞产生 IFN-γ阳性淋巴细胞的数量，但对供体小鼠的同源性淋巴细胞没有影响。输注经初始免疫的供体淋巴细胞可显著抑制受者小鼠的肿瘤生长，并使 64%的治疗小鼠得到治愈。自体 HSCT 联合输注经初始免疫的供体淋巴细胞是诱导实体瘤有效抗肿瘤免疫的一种有前途的策略。
