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Natural killer cells regulate distinct CD8+ T cell differentiation program in cancer and contribute to resistance against immune checkpoint blockers

ABSTRACT: Immune checkpoint blockers (ICBs) targeting the PD-1/PD-L1 axis represent established therapies for many cancers. However, resistance occurs in most patients due to multiple complex immune-suppressive mechanisms in the tumor microenvironment (TME). Natural killer (NK) cells can play effector roles in tumor control, but their impact on T cell dysfunction and ICB efficacy remains controversial. Through genetic and antibody-mediated NK cell depletion, we found that NK cells play negative roles in ICB sensitivity; they further impede CD8+ T cell differentiation toward CD69+ BCL2+ EOMES+ GZMB+ TIM3- GITR- CTLA4- phenotype. Mechanistically, we identified that the retinoic acid receptor alpha (RARα)-dependent differentiation program in CD8+ T cells is hindered due to cytokine competition with NK cells. Finally, we observed that lower frequencies of NK cells correlate with better clinical response to ICBs in cancer patients. These findings suggest a potential avenue for enhancing CD8+ T cell-centered immunotherapy by targeting NK cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE284356 | GEO | 2025/02/01

REPOSITORIES: GEO

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Project description:Introduction Immune checkpoint blockade (ICB) is a systemic therapeutic option for advanced hepatocellular carcinoma (HCC). However, low patient response rates necessitate the development of robust predictive biomarkers that identify individuals who will benefit from ICB. A 4-gene inflammatory signature, comprising CD8, PD-L1, LAG-3, and STAT1, was recently shown to be associated with a better overall response to ICB in various cancer types. Here, we examined whether tissue protein expression of CD8, PD-L1, LAG-3, and STAT1 predicts response to ICB in HCC. Methods HCC samples from 191 Asian patients, comprising resection specimens from 124 patients (ICB-naïve) and pre-treatment specimens from 67 advanced HCC patients treated with ICB (ICB-treated), were analyzed for CD8, PD-L1, LAG-3, and STAT1 tissue expression using multiplex immunohistochemistry followed by statistical and survival analyses. Results Immunohistochemical and survival analyses of ICB-naïve samples showed that high LAG-3 expression was associated with shorter median progression-free survival (mPFS) and overall survival (mOS). Analysis of ICB-treated samples revealed that high proportions of LAG-3+ and LAG-3+CD8+ cells pre-treatment were most closely associated with longer mPFS and mOS. Using a log-likelihood model, adding the total LAG-3+ cell proportion to the total CD8+ cell proportion significantly increased the predictive values for mPFS and mOS, compared with the total CD8+ cell proportion alone. Moreover, levels of CD8 and STAT1, but not PD-L1, were significantly correlated with better responses to ICB. After analyzing viral-related and non-viral HCC samples separately, only the LAG3+CD8+ cell proportion was significantly associated with responses to ICB regardless of viral status. Conclusion Immunohistochemical scoring of pre-treatment levels of LAG-3 and CD8 in the tumor microenvironment may help predict ICB benefits in HCC patients. Furthermore, immunohistochemistry-based techniques offer the advantage of being readily translatable in the clinical setting.

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Natural killer cells regulate distinct CD8+ T cell differentiation program in cancer and contribute to resistance against immune checkpoint blockers

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