Paczkowska Julia, Tang Ming, Wright Kyle T, Song Li, Luu Kelsey, Shanmugam Vignesh, Welsh Emma L, Weirather Jason L, Besson Naomi, Olszewski Harrison, Porter Billie A, Pfaff Kathleen L, Redd Robert A, Cader Fathima Zumla, Mandato Elisa, Ouyang Jing, Calabretta Eleonora, Bai Gali, Lawton Lee N, Armand Philippe, Rodig Scott J, Liu Xiaole Shirley, Shipp Margaret A
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA.
Nat Commun. 2024 Dec 30;15(1):10740. doi: 10.1038/s41467-024-54512-7.
Hodgkin Reed-Sternberg (HRS) cells of classic Hodgkin lymphoma (cHL), like many solid tumors, elicit ineffective immune responses. However, patients with cHL are highly responsive to PD-1 blockade, which largely depends on HRS cell-specific retention of MHC class II and implicates CD4 T cells and additional MHC class I-independent immune effectors. Here, we utilize single-cell RNA sequencing and spatial analysis to define shared circulating and microenvironmental features of the immune response to PD-1 blockade in cHL. Compared with non-responders, responding patients have more circulating CD4 naïve and central memory T cells and B cells, as well as more diverse CD4 T cell and B cell receptor repertoires. Importantly, a population of circulating and tumor-infiltrating IL1β monocytes/macrophages is detectable in patients with cHL but not healthy donors, and a proinflammatory, tumor-promoting signature of these circulating IL1β monocytes is associated with resistance to PD-1 blockade in cHL. Altogether, our findings reveal extensive immune rewiring and complementary roles of CD4 T cells, B cells and IL1β monocytes in the response to PD-1 blockade and suggest that these features can be captured with a peripheral blood test.
与许多实体瘤一样，经典型霍奇金淋巴瘤（cHL）中的霍奇金里德-斯腾伯格（HRS）细胞引发的免疫反应无效。然而，cHL患者对程序性死亡受体1（PD-1）阻断治疗高度敏感，这在很大程度上取决于HRS细胞对II类主要组织相容性复合体（MHC）的特异性保留，并涉及CD4 T细胞和其他不依赖I类MHC的免疫效应细胞。在这里，我们利用单细胞RNA测序和空间分析来确定cHL中对PD-1阻断的免疫反应的共同循环和微环境特征。与无反应者相比，有反应的患者有更多循环中的初始CD4 T细胞、中央记忆T细胞和B细胞，以及更多样化的CD4 T细胞和B细胞受体库。重要的是，在cHL患者而非健康供者中可检测到一群循环和肿瘤浸润的白细胞介素1β（IL1β）单核细胞/巨噬细胞，这些循环IL1β单核细胞的促炎、肿瘤促进特征与cHL中对PD-1阻断的抗性相关。总之，我们的研究结果揭示了在对PD-1阻断的反应中CD4 T细胞、B细胞和IL1β单核细胞的广泛免疫重塑和互补作用，并表明这些特征可以通过外周血检测来捕捉。
