Immuno-oncology, Beckman Research Institute City of Hope, Duarte, California, USA.
Medical Oncology, City of Hope National Medical Center, Duarte, California, USA.
J Immunother Cancer. 2021 Mar;9(3). doi: 10.1136/jitc-2020-002084.
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.
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.
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.
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.
NCT02778685 and NCI02648477.
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。
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。
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。
HR+MBC 患者接受派姆单抗和帕博西尼联合治疗的反应与循环效应 CD8 和 CD4 T 细胞的预先存在和循环髓样细胞组成的动态调节有关。
NCT02778685 和 NCI02648477。
