Multimodal immunopharmacologic screens identify drugs rewiring the cancer-immune interface

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Natural killer (NK) cell therapies show promise for cancer treatment but face challenges due to impaired effector function and tumor resistance.
• Developing strategies to address both the immune cells and the tumor is crucial for improving therapeutic efficacy.

Purpose of the Study:

• To systematically identify therapeutic strategies that enhance NK cell-mediated cancer immunity by targeting both the cancer and immune cells.
• To develop and apply a multimodal immunopharmacologic screening platform for discovering novel cancer immunotherapies.

Main Methods:

• A multimodal screening platform was developed, including high-throughput co-culture drug screens, cytokine secretome profiling, single-cell perturbation screens, and genome-scale CRISPR screening.
• The platform was applied to five blood cancer types, with validation in patient-derived models.
• Analysis involved transcriptomic rewiring, assessment of tumor-intrinsic resistance, and evaluation of drug effects on immune signaling pathways.

Main Results:

• Protein kinase C (PKC) activation was identified as a strategy that simultaneously enhances NK cell cytotoxicity and cytokine secretion while increasing tumor susceptibility to NK cell killing.
• PKC activation sensitized NK-resistant leukemic progenitors to NK cell-mediated killing in patient samples.
• NEDD8 inhibition was found to enhance NK cell function and promote pro-apoptotic TNF signaling in tumors.

Conclusions:

• The developed screening platform offers a systematic approach to identify drugs that can overcome tumor immune resistance by modulating both cancer cells and immune cells.
• Targeting pathways like PKC and NEDD8 presents a viable strategy for enhancing the efficacy of NK cell-based cancer immunotherapies.