Blood and Marrow Transplant Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Blood and Marrow Transplant Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Biol Blood Marrow Transplant. 2014 Jan;20(1):26-36. doi: 10.1016/j.bbmt.2013.10.009. Epub 2013 Oct 17.
The clinical success of allogeneic T cell therapy for cancer relies on the selection of antigens that can effectively elicit antitumor responses with minimal toxicity toward nonmalignant tissues. Although minor histocompatibility antigens (MiHA) represent promising targets, broad expression of these antigens has been associated with poor responses and T cell dysfunction that may not be prevented by targeting MiHA with limited expression. In this study, we hypothesized that antitumor activity of MiHA-specific CD8 T cells after allogeneic bone marrow transplantation (BMT) is determined by the distribution of antigen relative to the site of tumor growth. To test this hypothesis, we utilized the clinically relevant male-specific antigen HY and studied the fate of adoptively transferred, HY-CD8(+) T cells (HY-CD8) against a HY-expressing epithelial tumor (MB49) and pre-B cell leukemia (HY-E2APBX ALL) in BMT recipients. Transplants were designed to produce broad HY expression in nonhematopoietic tissues (female → male BMT, [F → M]), restricted HY expression in hematopoietic tissues (male → female BMT, [M → F]) tissues, and no HY tissue expression (female → female BMT, [F → F]). Broad HY expression induced poor responses to MB49 despite sublethal graft-versus-host disease and accumulation of HY-CD8 in secondary lymphoid tissues. Antileukemia responses, however, were preserved. In contrast, restriction of HY expression to hematopoietic tissues restored MB49 responses but resulted in a loss of antileukemia responses. We concluded that target alloantigen expression in the same compartment of tumor growth impairs CD8 responses to both solid and hematologic tumors.
同种异体 T 细胞疗法治疗癌症的临床成功依赖于选择能够有效引发抗肿瘤反应且对非恶性组织毒性最小的抗原。虽然次要组织相容性抗原 (MiHA) 代表了有前途的靶标，但这些抗原的广泛表达与较差的反应和 T 细胞功能障碍相关，而通过针对表达有限的 MiHA 可能无法预防这些问题。在这项研究中，我们假设同种异体骨髓移植 (BMT) 后 MiHA 特异性 CD8 T 细胞的抗肿瘤活性取决于抗原相对于肿瘤生长部位的分布。为了验证这一假设，我们利用了临床相关的雄性特异性抗原 HY，并研究了过继转移的 HY-CD8(+) T 细胞 (HY-CD8) 对表达 HY 的上皮肿瘤 (MB49) 和前 B 细胞白血病 (HY-E2APBX ALL) 的命运，在 BMT 受者中。移植设计旨在使非造血组织中广泛表达 HY（女性→男性 BMT，[F→M]）、限制造血组织中 HY 表达（男性→女性 BMT，[M→F]）和无 HY 组织表达（女性→女性 BMT，[F→F]）。尽管存在亚致死性移植物抗宿主病和 HY-CD8 在次级淋巴组织中的积累，但广泛的 HY 表达诱导了对 MB49 的反应不佳。然而，保留了抗白血病反应。相比之下，将 HY 表达限制在造血组织中恢复了对 MB49 的反应，但导致抗白血病反应丧失。我们得出结论，肿瘤生长相同部位的靶抗原表达会损害对实体瘤和血液系统肿瘤的 CD8 反应。
