Shift in Tissue-Specific Immune Niches and CD137 Expression in Tuberculoma of Pembrolizumab-Treated Nasopharyngeal Carcinoma Patients

Simple Summary Despite that a paradoxical response of immune checkpoint inhibition (ICI) is tuberculosis (TB) reactivation, our knowledge of cross-compartmental immune cellularity in human tissues remains limited. Existing studies mainly focused on treatment-associated malignant transformation or TB persistence. Unifying cellular heterogeneity across healthy and pathological tissues is crucial for developing treatments that overcome ICIs-related adverse events. In this study, we highlight the complexity of anti-PD1 functions, which go beyond enhancing immunity solely within the tumor microenvironment (TME) and can be influenced by shifts in CD137-rich immune niches. Each pathological lesion exhibited a unique tissue-specific immune microenvironment (TSIME) associated with ICI, emphasizing the need to tailor cancer therapy considering the characteristics of each TSIME for effective treatment. We also provide evidence of a niche-shift in the CD137-rich hostile TSIME, which may contribute to the reactivation of TB associated with ICI treatment. These findings serve as proof-of-concept for the potential clinical development of selectively activating anti-CD137 signaling within the TME, in combination with checkpoint blockade.Abstract 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 IFN gamma 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 IFN gamma+ 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.