Dataset Information

Phosphoproteomic analysis of IL-2 MSA and IL-12 MSA combination on T cell signaling

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Spleen, T Cell

SUBMITTER: Alicia Dsouza

LAB HEAD: Forest White

PROVIDER: PXD044740 | Pride | 2024-01-26

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	BH_AD_IL2IL12MSA.msf	Msf
	BH_AD_IL2IL12MSA.mzML	Mzml
	BH_AD_IL2IL12MSA.mzid.gz	Mzid
	BH_AD_IL2IL12MSA.raw	Raw
	BH_AD_IL2IL12MSA_TMTChannelInfo.xlsx	Xlsx

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Publications

Overcoming lung cancer immunotherapy resistance by combining nontoxic variants of IL-12 and IL-2.

Horton Brendan L BL D'Souza Alicia D AD Zagorulya Maria M McCreery Chloe V CV Abhiraman Gita C GC Picton Lora L Sheen Allison A Agarwal Yash Y Momin Noor N Wittrup K Dane KD White Forest M FM Garcia K Christopher KC Spranger Stefani S

JCI insight 20231009 19

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) because of low IL-12 receptor (IL-12R) expression on tumor-reactive CD8+ T cells. IL2-MSA increased binding of IL12-MSA by tumor-reactive CD8+ ...[more]

PMID: 37669107

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