The use of immune checkpoint inhibitors (ICIs) in cancer treatment has shown promise but can also have unintended consequences, such as reactivating latent tuberculosis (TB). To develop treatments that address ICIs-related adverse events, it is essential to understand cellular heterogeneity across healthy and pathological tissues. We performed cross-tissue multiplexed staining analysis on samples from two patients with TB reactivation during pembrolizumab treatment for metastatic nasopharyngeal carcinoma. CD8+ T cells, rather than CD4+ T cells, accumulated preferentially in the tuberculoma and were associated with increased production of IFNγ and expression of CD137. Additionally, CD137 enrichment played a role in the spatial organization of the tuberculoma, with specific interaction limited to spatial proximal cells between IFNγ+ CD137+ CD8+ T cells and IL12+ CD137+ type-1 macrophages. This unique feature was not observed in non-tumoral or tumoral tissues. Our analysis of public transcriptomic datasets supported the notion that this cellular interaction was more prominent in patients with durable ICI responses compared to those with non-ICI-related TB. We suggest that shifts towards CD137-rich immune niches are correlated with both off-target immune-related adverse events and anti-tumor efficacy. Targeting the tumor microenvironment through conditional activation of anti-CD137 signaling in combination with ICIs can modulate the reactivity of T cells and macrophages for localized tumor killing without the potential off-target immune-related risks associated with ICIs alone.
免疫检查点抑制剂（ICIs）在癌症治疗中的应用显示出前景，但也可能产生意外后果，例如重新激活潜伏的结核病（TB）。为了开发针对ICIs相关不良事件的治疗方法，理解健康和病理组织间的细胞异质性至关重要。我们对两名在转移性鼻咽癌接受帕博利珠单抗治疗期间出现结核病再激活患者的样本进行了跨组织多重染色分析。CD8+ T细胞（而非CD4+ T细胞）优先在结核瘤中聚集，并与IFNγ产量增加及CD137表达相关。此外，CD137富集在结核瘤的空间组织中发挥作用，IFNγ+ CD137+ CD8+ T细胞与IL12+ CD137+ 1型巨噬细胞之间的特异性相互作用仅限于空间邻近细胞。这一独特特征在非肿瘤或肿瘤组织中未被观察到。我们对公共转录组数据集的分析支持这一观点：与非ICIs相关结核病患者相比，这种细胞相互作用在具有持久ICIs反应的患者中更为显著。我们认为，向富含CD137的免疫微环境的转变与脱靶免疫相关不良事件及抗肿瘤疗效均相关。通过条件性激活抗CD137信号通路联合ICIs靶向肿瘤微环境，可以调节T细胞和巨噬细胞的反应性以实现局部肿瘤杀伤，同时避免单独使用ICIs可能带来的脱靶免疫相关风险。
肿瘤(癌症)患者之家