Targeting MAL2-mediated endocytosis to enhance tumor cell antigen presentation

项目摘要 癌症免疫治疗是一种很有前途的方法，适用于没有或有限特异性靶向治疗的癌症。 各种形式的免疫疗法，包括检查站封锁免疫疗法，都被证明是有效的。 通过增强T细胞介导的免疫反应。这些疗法导致显著和持续的临床 反应，但仅限于有限数量的患者和癌症类型。抗肿瘤免疫反应需要 肿瘤抗原的功能呈现和有利于有能力的免疫效应器的微环境。至 CD8+细胞毒性T淋巴细胞(CTL)对肿瘤细胞的杀伤作用 在癌细胞的主要组织相容性复合体I类(MHC-I)复合体上发表，并触发 癌细胞经历程序性细胞死亡。为了逃避免疫监视，癌细胞使用了各种 直接或间接下调MHC-I分子或其他蛋白质表达的机制 在抗原处理和呈递方面。下调监管似乎比完全消除监管更常见 MHC-I的表达减少，因为后者使癌细胞更容易受到自然杀伤(NK)细胞的作用。 增加肿瘤细胞上的抗原提呈可能具有治疗意义，因为它使肿瘤细胞 对CTL敏感。 在初步研究中，我们确定了一种膜蛋白MAL2，它是一个重要的角色，可以减少 乳腺癌细胞的抗原递呈和抑制肿瘤浸润性CD8+T细胞的细胞毒作用。至 为了促进MAL2抑制的临床前研究，我们已经产生了针对小鼠的单抗 MAL2。我们将在小鼠乳腺肿瘤模型中检测MAL2抑制剂(MAL2 MAb)的抗肿瘤作用。我们会 同时测定MAL2抑制剂增强免疫检查点疗效的治疗活性 封锁免疫疗法。

Project Abstract Cancer immunotherapy is a promising approach for cancers with no or limited specific targeted therapies. Various forms of immunotherapy, including checkpoint blockade immunotherapies, are proving to be effective by boosting T cell-mediated immune responses. These therapies lead to marked and sustained clinical responses, but only in a limited number of patients and cancer types. Anti-tumor immune responses require functional presentation of tumor antigens and a microenvironment that favors competent immune effectors. To execute the cytotoxicity on cancer cells, the CD8+ cytotoxic T lymphocytes (CTLs) recognize tumor antigens presented on the major histocompatibility complex class I (MHC-I) complex of the cancer cell and trigger the cancer cell to undergo programmed cell death. To evade immune surveillance, cancer cells employ various mechanisms to downregulate the expression of MHC-I molecules or other proteins directly or indirectly involved in antigen processing and presentation. Downregulation appears to be more common than complete elimination of MHC-I expression because the latter renders cancer cells susceptible to the action of natural killer (NK) cells. Increased antigen presentation on tumor cells can be of therapeutic significance since it makes tumor cells more susceptible to the CTLs. In the preliminary study, we identified a membrane protein, MAL2, as an important player that reduces the antigen presentation on breast cancer cells and suppresses the cytotoxicity of tumor-infiltrating CD8+ T cells. To facilitate the preclinical studies for MAL2 inhibition, we have generated monoclonal antibodies against the mouse MAL2. We will test the antitumor effect of MAL2 inhibitor (MAL2 mAb) in mouse breast tumor models. We will also determine the therapeutic activity of MAL2 inhibitor in enhancing the efficacy of immune checkpoint blockade immunotherapy.