PXD044740

PXD044740 is an original dataset announced via ProteomeXchange.

Title	Phosphoproteomic analysis of IL-2 MSA and IL-12 MSA combination on T cell signaling
Description	Engineered cytokine-based approaches for immunotherapy of cancer are poised to enter the clinic, with IL-12 being at the forefront. However, little is known about potential mechanisms of resistance to cytokine therapies. We found that orthotopic murine lung tumors were resistant to systemically delivered IL-12 fused to murine serum albumin (MSA, IL12-MSA) due to low IL-12R expression on tumor-reactive CD8+ T cells. IL2-MSA increased binding of IL12-MSA by tumor-reactive CD8+ T cells, and combined administration of IL12-MSA and IL2-MSA led to enhanced tumor-reactive CD8+ T cell effector differentiation, decreased numbers of tumor-infiltrating CD4+ regulatory T (Treg) cells, and increased survival of lung tumor-bearing mice. Predictably, the combination of IL-2 and IL-12 at therapeutic doses led to significant dose-limiting toxicity. Administering IL-12 and IL-2 analogs with preferential binding to cells expressing IL12rb1 and CD25, respectively, led to a significant extension of survival in mice with lung tumors while abrogating dose-limiting toxicity. These findings suggest that IL-12 and IL-2 represent a rational approach to combination cytokine therapy whose dose-limiting toxicity can be overcome with engineered cytokine variants.
HostingRepository	PRIDE
AnnounceDate	2024-01-26
AnnouncementXML	Submission_2024-01-26_05:52:07.383.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD044740
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Alicia Dsouza
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2023-08-22 07:37:41	ID requested
⏵ 1	2024-01-26 05:52:08	announced

Horton BL, D'Souza AD, Zagorulya M, McCreery CV, Abhiraman GC, Picton L, Sheen A, Agarwal Y, Momin N, Wittrup KD, White FM, Garcia KC, Spranger S, Overcoming lung cancer immunotherapy resistance by combining nontoxic variants of IL-12 and IL-2. JCI Insight, 8(19):(2023) [pubmed]

10.1172/jci.insight.172728;

10.6019/PXD044740;

submitter keyword: Signaling, T cell,Cytokine

Forest White
contact affiliation	Professor, Bioengineering, Massachusetts Institute of Technology
contact email	fwhite@mit.edu
lab head
Alicia Dsouza
contact affiliation	Massachussetts Institute of Technology
contact email	adsouza@mit.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD044740
     1. Label: PRIDE project
     2. Name: Phosphoproteomic analysis of IL-2 MSA and IL-12 MSA combination on T cell signaling