预先存在的效应 T 细胞水平和增强的髓样细胞组成预示着激素受体阳性转移性乳腺癌对 CDK4/6 抑制剂 palbociclib 和 pembrolizumab 的反应。

Pre-existing effector T-cell levels and augmented myeloid cell composition denote response to CDK4/6 inhibitor palbociclib and pembrolizumab in hormone receptor-positive metastatic breast cancer.

机构信息

Immuno-oncology, Beckman Research Institute City of Hope, Duarte, California, USA.

Medical Oncology, City of Hope National Medical Center, Duarte, California, USA.

出版信息

J Immunother Cancer. 2021 Mar;9(3). doi: 10.1136/jitc-2020-002084.

DOI:10.1136/jitc-2020-002084

PMID:33757987

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7993344/

Abstract

BACKGROUND

Single-agent pembrolizumab treatment of hormone receptor-positive metastatic breast cancer (MBC) has demonstrated modest clinical responses. Little is known about potential biomarkers or mechanisms of response to immune checkpoint inhibitors (ICIs) in patients with HR+ MBC. The present study presents novel immune correlates of clinical responses to combined treatment with CDK4/6i and ICI.

METHODS

A combined analysis of two independent phase I clinical trials treating patients with HR+ MBC was performed. Patients treated with the combination of the CDK4/6i palbociclib+the ICI pembrolizumab+the aromatase inhibitor (AI) letrozole (palbo+pembro+AI) were compared with patients treated with pembrolizumab+AI (pembro+AI). Peripheral blood mononuclear cells collected at pretreatment, 3 weeks (cycle 2 day 1) and 9 weeks (cycle 4 day 1) were characterized by high-parameter flow cytometry to assess baseline immune subset composition and longitudinal changes in response to therapy.

RESULTS

In the peripheral blood, higher pretreatment frequencies of effector memory CD45RA CD8 T cells and effector memory CD4 T cells were observed in responders to palbo+pembro+AI. In contrast, this was not observed in pembro+AI-treated patients. We further characterized T-cell subsets of effector-like killer cell lectin-like receptor subfamily G member 1 (KLRG1) ICOS CD4 T cells and KLRG1 CD45RA CD8 T cells as baseline biomarkers of response. In comparison, pretreatment levels of tumor-infiltrating lymphocyte, tumor mutation burden, tumor programmed death-ligand 1 expression, and overall immune composition did not associate with clinical responses. Over the course of treatment, significant shifts in myeloid cell composition and phenotype were observed in palbo+pembro+AI-treated patients, but not in those treated with pembro+AI. We identified increased fractions of type 1 conventional dendritic cells (cDC1s) within circulating dendritic cells and decreased classical monocytes (cMO) within circulating monocytes only in patients treated with palbociclib. We also demonstrated that in palbociclib-treated patients, cDC1 and cMO displayed increased CD83 and human leukocyte antigen-DR isotype (HLA-DR) expression, respectively, suggesting increased maturation and antigen presentation capacity.

CONCLUSIONS

Pre-existing circulating effector CD8 and CD4 T cells and dynamic modulation of circulating myeloid cell composition denote response to combined pembrolizumab and palbociclib therapy for patients with HR+ MBC.

TRIAL REGISTRATION NUMBER

NCT02778685 and NCI02648477.

摘要

背景

单药派姆单抗治疗激素受体阳性转移性乳腺癌（MBC）显示出适度的临床反应。对于 HR+MBC 患者对免疫检查点抑制剂（ICI）的潜在生物标志物或反应机制知之甚少。本研究提出了联合治疗 CDK4/6i 和 ICI 的临床反应的新型免疫相关性。

方法

对治疗 HR+MBC 的两项独立的 I 期临床试验进行联合分析。比较了接受 CDK4/6i 帕博西尼+ICI 派姆单抗+芳香酶抑制剂（AI）来曲唑（帕博西尼+派姆单抗+AI）治疗的患者与接受派姆单抗+AI（派姆单抗+AI）治疗的患者。在预处理、3 周（第 2 周期 1 天）和 9 周（第 4 周期 1 天）采集外周血单核细胞，通过高参数流式细胞术评估基线免疫亚群组成和对治疗的纵向变化。

结果

在接受 palbo+pembro+AI 治疗的患者中，效应记忆 CD45RA CD8 T 细胞和效应记忆 CD4 T 细胞的预处理频率较高。相比之下，在接受 pembro+AI 治疗的患者中没有观察到这种情况。我们进一步将效应样杀伤细胞凝集素样受体亚家族 G 成员 1（KLRG1）ICOS CD4 T 细胞和 KLRG1 CD45RA CD8 T 细胞的 T 细胞亚群特征作为反应的基线生物标志物。相比之下，肿瘤浸润淋巴细胞、肿瘤突变负担、肿瘤程序性死亡配体 1 表达和整体免疫组成均与临床反应无关。在治疗过程中，在接受 palbo+pembro+AI 治疗的患者中观察到髓样细胞组成和表型的显著变化，但在接受 pembro+AI 治疗的患者中未观察到这种变化。我们发现，仅在接受 palbociclib 治疗的患者中，循环树突状细胞内的 1 型传统树突状细胞（cDC1）和循环单核细胞内的经典单核细胞（cMO）比例增加。我们还证明，在接受 palbociclib 治疗的患者中，cDC1 和 cMO 分别显示出 CD83 和人类白细胞抗原-DR 同种型（HLA-DR）表达增加，表明成熟和抗原呈递能力增强。