Barnas Jennifer L, Simpson-Abelson Michelle R, Yokota Sandra J, Kelleher Raymond J, Bankert Richard B
Department of Microbiology and Immunology, Witebsky Center, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, 138 Farber Hall, 3435 Main Street, Buffalo, NY 14214 USA.
Cancer Microenviron. 2010 Mar 31;3(1):29-47. doi: 10.1007/s12307-010-0044-5.
The immune system of cancer patients recognizes tumor-associated antigens expressed on solid tumors and these antigens are able to induce tumor-specific humoral and cellular immune responses. Diverse immunotherapeutic strategies have been used in an attempt to enhance both antibody and T cell responses to tumors. While several tumor vaccination strategies significantly increase the number of tumor-specific lymphocytes in the blood of cancer patients, most vaccinated patients ultimately experience tumor progression. CD4+ and CD8+ T cells with an effector memory phenotype infiltrate human tumor microenvironments, but most are hyporesponsive to stimulation via the T cell receptor (TCR) and CD28 under conditions that activate memory T cells derived from the peripheral blood of the cancer patients or normal donors. Attempts to identify cells and molecules responsible for the TCR signaling arrest of tumor-infiltrating T cells have focused largely upon the immunosuppressive effects of tumor cells, tolerogenic dendritic cells and regulatory T cells. Here we review potential mechanisms by which human T cell function is arrested in the tumor microenvironment with a focus on the immunomodulatory effects of stromal fibroblasts. Determining in vivo which cells and molecules are responsible for the TCR arrest in human tumor-infiltrating T cells will be necessary to formulate and test strategies to prevent or reverse the signaling arrest of the human T cells in situ for a more effective design of tumor vaccines. These questions are now addressable using novel human xenograft models of tumor microenvironments.
癌症患者的免疫系统能够识别实体瘤上表达的肿瘤相关抗原，这些抗原能够诱导肿瘤特异性的体液免疫和细胞免疫反应。人们采用了多种免疫治疗策略来增强抗体和T细胞对肿瘤的反应。虽然几种肿瘤疫苗接种策略显著增加了癌症患者血液中肿瘤特异性淋巴细胞的数量，但大多数接种疫苗的患者最终还是出现了肿瘤进展。具有效应记忆表型的CD4+和CD8+ T细胞浸润人类肿瘤微环境，但在激活源自癌症患者或正常供体外周血的记忆T细胞的条件下，大多数细胞对通过T细胞受体（TCR）和CD28的刺激反应低下。识别负责肿瘤浸润性T细胞TCR信号传导停滞的细胞和分子的尝试主要集中在肿瘤细胞、耐受性树突状细胞和调节性T细胞的免疫抑制作用上。在这里，我们综述了人类T细胞功能在肿瘤微环境中停滞的潜在机制，重点关注基质成纤维细胞的免疫调节作用。确定体内哪些细胞和分子负责人类肿瘤浸润性T细胞中的TCR停滞，对于制定和测试预防或逆转人类T细胞原位信号传导停滞的策略以更有效地设计肿瘤疫苗是必要的。现在可以使用新型的人类肿瘤微环境异种移植模型来解决这些问题。
