Cell Reports
Volume 41, Issue 5, 1 November 2022, 111582
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Article
Mobilizing phospholipids on tumor plasma membrane implicates phosphatidylserine externalization blockade for cancer immunotherapy

https://doi.org/10.1016/j.celrep.2022.111582Get rights and content
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open access

Highlights

  • PSout tumors grow larger than WT, with an immune-suppressive tumor microenvironment

  • TIM-3 is responsible for PS sensing in PSout tumors

  • PSin tumors activate STING, leading to TAM M1 polarization and NK cell cytotoxicity

  • Silencing Xkr8 in vivo to block PS externalization provides anti-tumor effects in mice

Summary

In “healthy” tumor cells, phosphatidylserine (PS) is predominately localized in the inner plasma membrane leaflet. During apoptosis, PS relocates to the outer leaflet. Herein, we established PSout tumor models with tumor cells lacking PS flippase component CDC50A, constantly exposing PS but alive. PSout tumors developed bigger than wild-type (WT) tumors, featuring M2 polarized tumor-associated macrophages (TAMs) and fewer tumor-antigen-specific T cells. The PS receptor TIM-3 is responsible for PS recognition. Employing an opposite tumor model, PSin, with tumor cells lacking the PS scramblase Xkr8 and unable to expose PS during otherwise normal apoptosis, we find that the accumulated apoptotic tumor cells produce and release cyclic GAMP (cGAMP) to immune cells to activate the STING pathway, leading to TAM M1 polarization, suppressed interleukin (IL)-10 secretion, and natural killer (NK) cell cytotoxicity. Silencing Xkr8 in vivo by either short hairpin RNA (shRNA) or small interfering RNA (siRNA) to achieve a PS externalization blockade provides robust therapeutic anti-tumor efficiency.

Keywords

phosphatidylserine externalization
CDC50a
Xkr8
cancer immunotherapy
STING

Research topic

CP: Cancer

Data and code availability

The RNAseq data for TAMs (PSin) generated in this study were uploaded to GEO: GSE185591. The RNAseq data for TAMs (PSout) and NK cells (PSin) generated in this study were uploaded to GEO: GSE200752.

This paper does not report original code.

Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Cited by (0)

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Present address: Center for Discovery and Innovation Hackensack Meridian Health Nutley, NJ 07110

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Lead contact