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Retargeting IL-2 Signaling to NKG2D-Expressing Tumor-Infiltrating Leukocytes Improves Adoptive Transfer Immunotherapy
- Source :
- J Immunol
- Publication Year :
- 2020
-
Abstract
- Ex vivo expansion followed by reinfusion of tumor infiltrating leucocytes (TILs) has been utilized successfully for the treatment of multiple malignancies. Most protocols rely on the use of the cytokine interleukin-2 (IL-2) to expand TILs prior to reinfusion. In addition, TIL administration relies on systemic administration of IL-2 post-reinfusion to support transferred cell survival. The use of IL-2, however, can be problematic due to its preferential expansion of regulatory T and myeloid cells as well as its systemic side effects. Here we describe the use of a novel IL-2 mutant retargeted to NKG2D rather than the high affinity IL-2 receptor for TIL-mediated immunotherapy in a murine model of malignant melanoma. We demonstrate that the NKG2D-retargeted IL-2 (called OMCPmutIL-2) preferentially expands TIL-resident cytotoxic lymphocytes, such as CD8(+) T cells, NK cells, and γδT cells while wild-type IL-2 provides a growth advantage for CD4(+)Foxp3(+) T cells as well as myeloid cells. OMCPmutIL-2 expanded cytotoxic lymphocytes express higher levels of tumor homing receptors such as LFA-1, CD49a and CXCR3 which correlate with TIL localization to the tumor bed after intravenous injection. Consistent with this OMCPmutIL-2 expanded TILs provided superior tumor control compared to those expanded in wild-type IL-2. Our data demonstrate that adoptive transfer immunotherapy can be improved by rational retargeting of cytokine signaling to NKG2D expressing cytotoxic lymphocytes rather than indiscriminate expansion of all TILs.
- Subjects :
- Male
Adoptive cell transfer
medicine.medical_treatment
Immunology
chemical and pharmacologic phenomena
Mice, Transgenic
CXCR3
Article
03 medical and health sciences
Mice
0302 clinical medicine
Leukocytes
Immunology and Allergy
Medicine
Animals
Humans
Melanoma
business.industry
FOXP3
hemic and immune systems
Immunotherapy
medicine.disease
NKG2D
Adoptive Transfer
Mice, Inbred C57BL
Cytokine
NK Cell Lectin-Like Receptor Subfamily K
Cancer research
Interleukin-2
business
CD8
030215 immunology
Signal Transduction
Subjects
Details
- ISSN :
- 15506606
- Volume :
- 207
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Accession number :
- edsair.doi.dedup.....2e8243e1b74baeac526be7b4201b4b8c