Identification of Tissue-Resident Adaptive NK Cells and Their Association With Reduced Mortality Across Diverse Solid Tumors — ASN Events
  1. Schedule
  2. Poster Session One
  3. Identification of Tissue-Resident Adaptive NK Cells and Their Association With Reduced Mortality Across Diverse Solid Tumors

Identification of Tissue-Resident Adaptive NK Cells and Their Association With Reduced Mortality Across Diverse Solid Tumors (#161)

John Roy Lozada 1 , Atef Ali 1 , Christine Luo 1 , Rosemary N Plagens 2 , Andrew Elliott 2 , Ella Boytim 1 , Nicholas A Zorko 1 , Jeffrey S Miller 1 , Emmanuel S Antonarakis 1 , Justin H Hwang 1 , Frank Cichocki 1
  1. University of Minnesota, Minneapolis, MINNESOTA, United States
  2. Caris Life Sciences, Irving, Texas, United States

Recent studies have highlighted the functional diversity of NK cells in cancer. However, these predominantly focused on conventional CD56dim and CD56bright NK cells, leaving adaptive and tissue-resident (TR) subsets less defined.

Our prior work analyzing scRNA-seq from 276 patients across 14 cancer types identified six main NK cell subsets in tumors more representative of NK cell diversity. These included conventional CD56dim and CD56bright populations, alongside adaptive, TR CD56bright, TR adaptive, and a distinct TR population with both CD56bright and adaptive features.

Here, we sought to understand the clinical relevance of distinct NK cell populations across cancer. Applying signature-based deconvolution methods to bulk RNA-seq from 212,205 tumor samples, TR adaptive NK cells emerged as the most prognostic subset, with their abundance conferring a greater reduction in mortality risk than conventional CD56dim and CD56bright subsets. This trend was also observed in cohorts of head and neck, lung, and esophageal cancers, particularly those treated with immune checkpoint blockade. To uncover mechanisms underlying this clinical benefit, we re-examined our scRNA-seq data, which linked the differential outcomes to a balance between IFNG versus TGFB1 expression in NK cells, with TR adaptive subsets exhibiting the highest and lowest levels, respectively. This pattern was associated with distinct transcription factor activity, as AP-1 factors correlated with IFNG expression and MAF and C/EBP factors with TGFB1. TR adaptive subsets also displayed the highest chemokine and cytokine activity, alongside low stress response and inhibitory receptor expression, further supporting a unique functional status.

Altogether, we uncover a novel role for TR adaptive NK cells in cancer. Further work will elucidate mechanisms driving the formation and function of these unique NK cell populations. Our studies will not only inform future NK cell-based therapies but also inspire new directions for understanding the ever-expanding landscape of NK cell diversity.