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Published on: June 12, 2021
PKCδ Germline Variants and Genetic Deletion in Mice Augment Antitumor Immunity through Regulation of Myeloid Cells
Kyle R Cron1,2, Ayelet Sivan1,2, Keston Aquino-Michaels1,2
1Department of Pathology, The University of Chicago, Chicago, Illinois.
Abstract:
Based on the notion that hypomorphic germline genetic variants are linked to autoimmune diseases, we reasoned that novel targets for cancer immunotherapy might be identified through germline variants associated with greater T-cell infiltration into tumors. Here, we report that while investigating germline polymorphisms associated with a tumor immune gene signature, we identified protein kinase C delta (PKCδ) as a candidate. Genetic deletion of Prkcd in mice resulted in improved endogenous antitumor immunity and increased efficacy of anti-PD-L1. Single-cell RNA sequencing revealed myeloid cell expression of Prkcd, and PKCδ deletion caused a shift in macrophage gene expression from an M2-like to an M1-like phenotype. Conditional deletion of Prkcd in myeloid cells recapitulated improved tumor control that was augmented further with anti-PD-L1. Analysis of clinical samples confirmed an association between PRKCD variants and M1/M2 phenotype, as well as between a PKCδ knockout-like gene signature and clinical benefit from anti-PD-1. Our results identify PKCδ as a candidate therapeutic target that modulates myeloid cell states.
Insights
Novel cancer immunotherapy targets may emerge from studying germline variants. Researchers identified protein kinase C delta (PKCδ) as a key player, showing its deletion enhances anti-tumor immunity and immunotherapy efficacy in preclinical models.
Area of Science:
- Immunology
- Oncology
- Genetics
Background:
- Germline genetic variants are linked to autoimmune diseases.
- Investigating germline variants associated with tumor immune signatures may reveal cancer immunotherapy targets.
- Protein kinase C delta (PKCδ) was identified as a candidate target.
Purpose of the Study:
- To identify novel cancer immunotherapy targets by examining germline variants linked to T-cell infiltration.
- To investigate the role of protein kinase C delta (PKCδ) in anti-tumor immunity.
Main Methods:
- Genetic deletion of Prkcd in mice.
- Single-cell RNA sequencing to analyze myeloid cell gene expression.
- Conditional deletion of Prkcd in myeloid cells.
- Analysis of clinical samples for PRKCD variants and immune cell phenotypes.
Main Results:
- Prkcd deletion in mice improved endogenous anti-tumor immunity and anti-PD-L1 efficacy.
- PKCδ deletion shifted macrophage phenotype from M2-like to M1-like.
- Conditional myeloid-specific Prkcd deletion enhanced tumor control, especially with anti-PD-L1 treatment.
- Clinical samples showed PRKCD variants associated with M1/M2 phenotypes and anti-PD-1 benefit.
Conclusions:
- Protein kinase C delta (PKCδ) is a potential therapeutic target for cancer immunotherapy.
- PKCδ modulates myeloid cell states, influencing the tumor immune microenvironment.
- Targeting PKCδ may enhance the efficacy of immune checkpoint inhibitors like anti-PD-1/PD-L1.
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