Paper - Review

DOI: 10.1016/j.immuni.2020.05.001

Graphical Abstract

In Brief

The transcription landscape
← of tumor-infiltrating NK-cells
∵ Using single-cell RNA sequencing

∴ The transcription factor → HIF-1α
→ suppresses → 1⃣ IL-18-driven NK-κB signaling 2⃣ anti-tumor activity
← of tumor infiltrating NK-cells

Extended inhibition of HIF-1α
← in 1⃣ mouse 2⃣ human NK-cells
→ unleashes potent NK-cell effector function

Highlights

Hif1a deficiency
← in NK-cells
→ reduces tumor growth

Activated Hif1a -/- NK-cell
← in tumor
∵ scRNA-seq

NK-IL18-IFNG-high signature
→ correlates ← with increased survivial

Summary

Enhancing → immune cell function
← in tumors
→ remains a major challenge ← in cancer immunotherapy

Hypoxia
→ is a common feature ← of solid tumors
Cell
→ adapt ← by up-regulating the transcription factor → HIF-1α

The transcriptional landscape
← of mouse tumor-infiltrating NK-cells
← by using single-cell RNA sequecing

Conditional deletion of Hif1a ← in NK-cells
→ resulted in 1⃣ reduced (tumor growth) 2⃣ elevated expression of (activation markers) & (effector molecules) 3⃣ an enriched NK-κB pathway
← in tumor-infiltrating NK-cells

IL-18 ← from myeloid cells
→ was required
→ for 1⃣ NK-κB activation 2⃣ the enhanced anti-tumor activity of Hif1a NK-cells

Extended culture ← with an HIF-1α inhibitor
→ increased human NK-cell responses

Low HIF1A expression
→ was associated ← with high expression of IFNG
← in human tumor-infiltrating NK-cells

An enriched NK-IL18-IFNG signature
← in solid tumor
→ correlated ← with increased overall patient survival

∴ Inhibition of HIF-1α
→ unleashes NK-cell anti-tumor activity
→ could be exploited → for cancer therapy

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