Garcia Myrna G, Deng Yilun, Murray Clare, Reyes Ryan M, Padron Alvaro, Bai Haiyan, Kancharla Aravind, Gupta Harshita, Shen-Orr Shai, Curiel Tyler J
South Texas Medical Scientist Training Program, University of Texas Health, San Antonio, Texas, USA.
Graduate School of Biomedical Sciences, University of Texas Health, San Antonio, Texas, USA.
Aging Cancer. 2022 Mar;3(1):68-83. doi: 10.1002/aac2.12045. Epub 2022 Feb 25.
Aging is the biggest cancer risk, and immune checkpoint (IC) inhibition (ICI) is a revolutionary cancer immunotherapy approach. Nonetheless, there are limited preclinical/clinical data regarding aging effects on ICI outcomes or age effects on IC expression in different organs or tumors.
Flow cytometry assessed IC on immune and non-immune cells in various organs in young and aged BL6 mice. Comparisons: aged versus young naïve WT versus interferon- mice and WT challenged with B16F10 melanoma and treated with PD-1 or PD-L1 ICI. We co-cultured young and aged T cells and myeloid cells in vitro and used OMIQ analyses to test cell-cell interactions.
PD-1 ICI treated melanoma in young and aged hosts, whereas PD-L1 ICI was only effective in young. We found considerable, previously undescribed age effects on expression of various IC molecules participating in the ICI treatment, including PD-1, PD-L1, PD-L2, and CD80, in distinct organs and in the tumor. These data help explain differential ICI efficacy in young and aged hosts. Host interferon- influenced age effects on IC expression in both directions depending on specific IC molecule and tissue. IC expression was further affected by tumor challenge on immune, non-immune, and tumor cells in tumor and other organs. In in vitro co-culture, PD-1 versus PD-L1 distinctly influenced polyclonal T cells in young versus aged, suggesting mechanisms for distinct age-related ICI outcomes.
Age affects IC expression on specific immune cells in an organ- and tissue-specific manner. ICs were generally higher on aged immune cells. High immune-cell PD-1 could help explain PD-1 efficacy in aged. High co-expression of CD80 with PD-L1 on dendritic cells could help explain lack of PD-L1 efficacy in aged hosts. Factors other than myeloid cells and interferon- also affect age-related IC expression and T cell function, meriting additional studies.
衰老乃最大的癌症风险因素，免疫检查点（IC）抑制（ICI）是一种革命性的癌症免疫治疗方法。然而，关于衰老对ICI疗效的影响或年龄对不同器官或肿瘤中IC表达的影响，临床前/临床数据有限。
采用流式细胞术评估年轻和老年BL6小鼠各器官免疫细胞和非免疫细胞上的IC。比较对象包括：老年与年轻、未致敏野生型（WT）与干扰素 - 小鼠，以及接种B16F10黑色素瘤并用PD - 1或PD - L1 ICI治疗的WT小鼠。我们在体外共培养年轻和老年T细胞及髓样细胞，并使用OMIQ分析来测试细胞间相互作用。
PD - 1 ICI可治疗年轻和老年宿主的黑色素瘤，而PD - L1 ICI仅对年轻宿主有效。我们发现，在不同器官和肿瘤中，参与ICI治疗的各种IC分子（包括PD - 1、PD - L1、PD - L2和CD80）的表达存在显著的、此前未被描述的年龄相关影响。这些数据有助于解释ICI在年轻和老年宿主中的疗效差异。宿主干扰素 - 根据特定的IC分子和组织，在两个方向上影响年龄对IC表达的作用。肿瘤攻击会进一步影响肿瘤及其他器官中免疫细胞、非免疫细胞和肿瘤细胞上的IC表达。在体外共培养中，PD - 1与PD - L1对年轻和老年多克隆T细胞的影响明显不同，这提示了与年龄相关的ICI疗效差异的机制。
年龄以器官和组织特异性方式影响特定免疫细胞上的IC表达。老年免疫细胞上的IC通常更高。免疫细胞上高表达的PD - 1有助于解释PD - 1在老年患者中的疗效。树突状细胞上CD80与PD - L1的高共表达可能有助于解释PD - L1在老年宿主中疗效不佳的原因。除髓样细胞和干扰素 - 外，其他因素也会影响与年龄相关的IC表达和T细胞功能，值得进一步研究。
