Targeting CD5 on Tumor-associated T and B cells to improve PD-1 blockade in Breast Cancer

项目摘要/摘要 三阴性乳腺癌(TNBC)是一种高度侵袭性的乳腺癌，具有 预后差，治疗有限。免疫检查点抑制，如程序化 死亡配体1(PD-L1)和受体程序性细胞死亡蛋白1(PD-1)是一种 最近在治疗包括TNBC在内的多种癌症方面取得了重大突破。阻断PD-1 抗体与PD-L1的相互作用显示出良好的临床效果。然而， 在TNBC患者中，对PD-1或PD-L1抗体的应答率仅为4.8%-26%。一个 提高PD-1抗体疗法等免疫疗法疗效的艰巨挑战是 关卡后如何将抑制CD8+T细胞转化为肿瘤浸润性杀伤细胞-- 强制刹车被移除。我们广泛的初步研究表明，持久性STAT3 激活是抑制先天和获得性抗肿瘤免疫的关键。烧蚀 T细胞中STAT3基因诱导CD8 Teff细胞肿瘤侵袭及抗肿瘤作用 效应器功能，主要是通过上调干扰素γ及其诱导因子发挥作用。 然而，转录因子STAT3抑制干扰素γ的机制尚不清楚。 直到我们最近发现STAT3直接上调肉碱棕榈酰转移酶1b (CPT1b)促进脂肪酸氧化，抑制糖酵解和干扰素γ表达 肿瘤CD8T细胞。然而，到目前为止，临床可用的STAT3抑制剂主要是JAK 抑制剂和JAK是干扰素γ触发的激活信号所必需的，从而导致 对效应细胞抗肿瘤活性可能需要的靶点进行更广泛的抑制。相比之下， CD5和PD-1抗体是受体/通路受限的，预计不会阻断JAK的激活 通过其他免疫刺激分子。初步数据表明，CD5和PD-1是协同作用的 在小鼠乳腺癌T细胞和B细胞上表达，CD5和PD-1均激活STAT3和 抑制干扰素γ，这是PD-1/PD-L1轴阻断治疗反应所必需的。这些 大量的数据使我们假设，在促进肿瘤的CD5+B细胞和T细胞中靶向CD5 细胞使PD-1抗体治疗有效地将STAT3显性/干扰素γ缺乏症转变为 干扰素γ富含抗乳腺癌小鼠模型的免疫活性。中心假说将 目的1.评估CD5/PD-1-STAT3在调控中的作用 FAO/糖酵解代谢与抑制CD8+T细胞抗肿瘤能力 功能。目的2.评估靶向CD5+B和T细胞的CD5是否会改变 代谢增强PD-1受体拮抗剂在小鼠乳腺中的抗乳腺癌作用 癌症模型。

PROJECT SUMMARY / ABSTRACT Triple negative breast cancer (TNBC) is a highly aggressive type of breast cancer that has a poor prognosis and limited treatment. Immune checkpoint inhibition, such as programmed death ligand 1 (PD-L1) and receptor programmed cell death protein 1 (PD-1), represents a major recent breakthrough in the treatment of diverse cancer including TNBC. Blocking PD-1 and PD-L1 interaction by antibodies has shown promising clinical effects. However, the response rate to PD-1 or PD-L1 antibody remains only at about 4.8%-26% in TNBC patients. A daunting challenge for improving efficacy of immunotherapy such as PD-1 antibody therapy is how to turn suppression CD8+ T cells to infiltrate tumor and kill tumor cells after the checkpoint- imposed brake is removed. Our extensive preliminary studies suggest that persistent STAT3 activation is critical for suppression of both innate and adaptive antitumor immunity. Ablating the Stat3 gene in T cells drastically induces CD8 TEFF cell tumor infiltration and antitumor effector functions, which mainly is through up-regulation of IFNγ and its inducible factors. However, the mechanism by which STAT3, a transcription factor, inhibits IFNγ remains unclear until we recently identified that STAT3 directly upregulates Carnitine palmitoyltransferase 1b (CPT1b) to promote fatty acid oxidation (FAO), which inhibits glycolysis and IFNγ expression in tumor CD8 T cells. However, to date clinically available STAT3 inhibitors are mainly JAK inhibitors, and JAKs are required for IFNγ triggered activation signaling, thus resulting in broader inhibition of targets that may be required for effector cell antitumor activities. In contrast, CD5 and PD-1 antibodies are receptor/pathway-limited and not expected to block JAK activation by other immunostimulatory molecules. Preliminary data indicate that CD5 and PD-1 are co- expressed on mouse breast cancer T and B cells, and both CD5 and PD-1 activate STAT3 and inhibit IFNγ which is necessary for therapeutic responses to PD-1/PD-L1 axis blockade. These extensive data led us to hypothesize that targeting CD5 in tumor-promoting CD5+ B cells and T cells enables PD-1 antibody therapy to effectively turn STAT3 dominance/IFNγ deficiency into IFNγ-rich anti-tumor immune activity in breast cancer mouse model. The central hypothesis will be tested in two aims: Aim 1. To assess the role of CD5/PD-1-STAT3 in regulating FAO/glycolysis metabolism and suppressing the CD8+ T cells capacity for anti-tumor function. Aim 2. To assess whether targeting CD5 on CD5+ B and T cells alters metabolism to enhance the anti-breast cancer effects of PD-1 blockade in mouse breast cancer model.