Mokyr M B, Kalinichenko T V, Gorelik L, Bluestone J A
Department of Biochemistry, University of Illinois at Chicago 60680, USA.
J Immunol. 1998 Feb 15;160(4):1866-74.
We have previously shown that low dose melphalan (L-phenylalanine mustard; L-PAM) therapy of hitherto immunosuppressed mice bearing a large (20-mm) s.c. MOPC-315 tumor leads to the acquisition of potent CD8+ T cell-mediated antitumor immunity which in turn eradicates the large tumor burden not eradicated by the direct antitumor effects of the drug. Here we show the preferential importance of the B7-2 costimulatory molecule for the curative effectiveness of low dose L-PAM for mice bearing a large MOPC-315 tumor by demonstrating that treatment with anti-B7-2 mAb, but not anti-B7-1 mAb, reduced the percentage of mice cured by the low dose L-PAM. In addition, we show the preferential importance of the B7-2 molecule for the low dose L-PAM-induced acquisition of the ability of tumor-infiltrating lymphocytes from MOPC-315 tumor bearers to secrete IL-2 and IFN-gamma as well as to exert an anti-MOPC-315 CTL effect. The preferential importance of the B7-2 molecule may be due to the higher level of B7-2 than of B7-1 expression on B220+ cells and on tumor cells from the s.c. tumor nodule of low dose L-PAM-treated MOPC-315 tumor bearers and the selective up-regulation of the B7-2 molecule in the draining of these mice. Thus, the B7-2 molecule plays a dominant role in the acquisition of T cell-dependent tumor-eradicating immunity in low dose L-PAM-treated mice bearing a large MOPC-315 tumor, suggesting that one of the mechanisms by which chemotherapy may enhance antitumor immunity is through up-regulation of critical costimulatory molecules that enhance antitumor responses.
我们之前已经表明，对先前免疫抑制且皮下接种大（20毫米）MOPC - 315肿瘤的小鼠进行低剂量美法仑（L - 苯丙氨酸氮芥；L - PAM）治疗，会导致获得强大的CD8⁺T细胞介导的抗肿瘤免疫力，进而消除药物直接抗肿瘤作用未消除的大肿瘤负荷。在此我们表明，通过证明用抗B7 - 2单克隆抗体而非抗B7 - 1单克隆抗体治疗会降低低剂量L - PAM治愈的小鼠百分比，B7 - 2共刺激分子对于低剂量L - PAM治疗携带大MOPC - 315肿瘤小鼠的疗效具有优先重要性。此外，我们表明B7 - 2分子对于低剂量L - PAM诱导MOPC - 315肿瘤携带者的肿瘤浸润淋巴细胞分泌白细胞介素 - 2和干扰素 - γ以及发挥抗MOPC - 315细胞毒性T淋巴细胞（CTL）效应的能力的获得具有优先重要性。B7 - 2分子的优先重要性可能归因于在低剂量L - PAM治疗的MOPC - 315肿瘤携带者的B220⁺细胞和皮下肿瘤结节的肿瘤细胞上，B7 - 2的表达水平高于B7 - 1，以及在这些小鼠的引流区中B7 - 2分子的选择性上调。因此，B7 - 2分子在低剂量L - PAM治疗携带大MOPC - 315肿瘤的小鼠获得T细胞依赖性肿瘤消除免疫力中起主导作用，这表明化疗增强抗肿瘤免疫力的机制之一可能是通过上调增强抗肿瘤反应的关键共刺激分子。
