Tinoco Julio C, Saunders Harmony I, Werner Lauryn Rose, Sun Xiaopeng, Chowanec Eilidh I, Heard Amanda, Chalise Prabhakar, Vahrenkamp Jeffery M, Wilson Andrea E, Liu Cong-Xiao, Lei Gangjun, Wei Junping, Cros Hugo, Mohammed Hisham, Troester Melissa, Perou Charles, Markiewicz Mary A, Gertz Jason, Balko Justin M, Hartman Zachary Conrad, Hagan Christy R
Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas, USA.
Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas, USA.
J Immunother Cancer. 2025 Mar 18;13(3):e010179. doi: 10.1136/jitc-2024-010179.
Breast cancer (BC) continues to be a major health concern with 250,000 new cases diagnosed annually in the USA, 75% of which are hormone receptor positive (HR+), expressing estrogen receptor alpha (ER) and/or the progesterone receptor (PR). Although ER-targeted therapies are available, 30% of patients will develop resistance, underscoring the need for new non-ER/estrogen-based treatments. Notably, HR+BCs exhibit poor lymphocyte infiltration and contain an immunosuppressive microenvironment, which contributes to the limited efficacy of immunotherapies in HR+BC. In this study, we demonstrate that PR/progesterone signaling reduces major histocompatibility complex (MHC) Class I expression, facilitating immune evasion and escape from immune-based clearance of PR+tumors.
To determine the effect of PR/progesterone on MHC Class I expression, we treated human and mouse mammary tumor cell lines with progesterone and/or interferon (IFN) and measured expression of genes involved in antigen processing and presentation (APP), as well as surface MHC Class I expression. We used the OT-I/SIINFEKL model antigen system to measure the impact of progesterone on immune cell-mediated killing of modified tumor cells. We also analyzed two large BC clinical cohorts to determine how PR expression correlates with APP gene expression and MHC Class I expression in ER-positive tumors.
In vitro, we show that PR/progesterone signaling reduces APP gene expression and MHC class I expression in human and breast mammary tumor cell lines. PR-mediated attenuation of APP/MHC Class I expression is more pronounced in the presence of IFN. In immune cell killing assays, PR-expressing mammary tumor cells treated with progesterone are protected from immune-mediated cytotoxicity. We demonstrate that PR expression in vivo prevents immune-mediated rejection of xenoantigen-modified mammary tumor cell lines through mechanisms involving MHC Class I expression and CD8 T cells. Data analysis of two large BC cohorts reveals lower APP gene expression and MHC Class I expression in ER/PR-positive tumors compared with ER-positive/PR-negative tumors. These findings show that HR+BCs, specifically PR+tumors, downregulate APP/MHC class I machinery through PR/progesterone signaling. Use of pharmacological PR/progesterone inhibitors may reverse these effects in patients with BC, thereby improving immunosurveillance and response to immunotherapies.
乳腺癌（BC）仍然是一个主要的健康问题，在美国每年有25万例新发病例，其中75%为激素受体阳性（HR+），表达雌激素受体α（ER）和/或孕激素受体（PR）。尽管有针对ER的治疗方法，但30%的患者会产生耐药性，这突出表明需要新的非基于ER/雌激素的治疗方法。值得注意的是，HR+乳腺癌表现出淋巴细胞浸润不良，并含有免疫抑制微环境，这导致免疫疗法在HR+乳腺癌中的疗效有限。在本研究中，我们证明PR/孕激素信号传导降低了主要组织相容性复合体（MHC）I类表达，促进了免疫逃逸以及PR+肿瘤从基于免疫的清除中逃脱。
为了确定PR/孕激素对MHC I类表达的影响，我们用孕激素和/或干扰素（IFN）处理人和小鼠乳腺肿瘤细胞系，并测量参与抗原加工和呈递（APP）的基因表达以及表面MHC I类表达。我们使用OT-I/SIINFEKL模型抗原系统来测量孕激素对免疫细胞介导的修饰肿瘤细胞杀伤的影响。我们还分析了两个大型乳腺癌临床队列，以确定PR表达与ER阳性肿瘤中APP基因表达和MHC I类表达之间的相关性。
在体外，我们表明PR/孕激素信号传导降低了人和乳腺肿瘤细胞系中的APP基因表达和MHC I类表达。在IFN存在的情况下，PR介导的APP/MHC I类表达减弱更为明显。在免疫细胞杀伤试验中，用孕激素处理的表达PR的乳腺肿瘤细胞受到保护，免受免疫介导的细胞毒性作用。我们证明，体内PR表达通过涉及MHC I类表达和CD8 T细胞的机制，防止了异种抗原修饰的乳腺肿瘤细胞系的免疫介导排斥。对两个大型乳腺癌队列的数据分析显示，与ER阳性/PR阴性肿瘤相比，ER/PR阳性肿瘤中的APP基因表达和MHC I类表达较低。这些发现表明，HR+乳腺癌，特别是PR+肿瘤，通过PR/孕激素信号传导下调APP/MHC I类机制。使用PR/孕激素药理学抑制剂可能会逆转乳腺癌患者的这些效应，从而改善免疫监视和对免疫疗法的反应。
