Spatial distribution of IL4 controls iNKT cell-DC crosstalk in tumors

Abstract

The spatiotemporal distribution of cytokines orchestrates immune responses in vivo, yet the underlying mechanisms remain to be explored. We showed here that the spatial distribution of interleukin-4 (IL4) in invariant natural killer T (iNKT) cells regulated crosstalk between iNKT cells and dendritic cells (DCs) and controlled iNKT cell-mediated T-helper type 1 (Th1) responses. The persistent polarization of IL4 induced by strong lipid antigens, that is, α-galactosylceramide (αGC), caused IL4 accumulation at the immunological synapse (IS), which promoted the activation of the IL4R-STAT6 (signal transducer and activator of transcription 6) pathway and production of IL12 in DCs, which enhanced interferon-γ (IFNγ) production in iNKT cells. Conversely, the nonpolarized secretion of IL4 induced by Th2 lipid antigens with a short or unsaturated chain was incapable of enhancing this iNKT cell-DC crosstalk and thus shifted the immune response to a Th2-type response. The nonpolarized secretion of IL4 in response to Th2 lipid antigens was caused by the degradation of Cdc42 in iNKT cells. Moreover, reduced Cdc42 expression was observed in tumorinfiltrating iNKT cells, which impaired IL4 polarization and disturbed iNKT cell-DC crosstalk in tumors.

Motility and tumor infiltration are key aspects of invariant natural killer T cell anti-tumor function

“…Elevated expression of Acvr1, Baiap2 and Fgd4 in intratumoral iNKT cells from Vcam1 knockdown MC38 tumors indicated improved CDC42 signaling, which is a Rho family small GTPase [43][44][45] . In line with previous study 46 , we found that expression of CDC42 was reduced in intratumoral iNKT cells (Fig. 5f).…”

Development of Plasmodium‐specific liver‐resident memory CD8+ T cells after heat‐killed sporozoite immunization in mice

“…α-GalCer is a synthetic glycolipid which binds to the nonclassical MHC-I molecule, CD1d, on APCs and activates Type 1 NKT cells. By activating NKT cells, the glycolipid α-GalCer induces maturation of DCs via CD40L presentation and cytokines such as IL-4, facilitating subsequent responses by conventional CD4 + and CD8 + T cells [38][39][40]. We chose α-GalCer as an adjuvant in the context of HKS vaccination because of its proven role in mediating protection against murine malaria [41] by enhancing malaria-specific CD8 + T-cell responses [33].…”

CAR-NKT cell therapy: a new promising paradigm of cancer immunotherapy

“…Crosstalk between these cells improves Th1 cell immune responses, which is mediated under the control of cell division control protein 42 homolog (Cdc42). The Cdc42 significantly controls cell migration and interaction, which decreased expression of Cdc42 in NKT cells and destroyed the intratumoral interaction and activation of NKT cells [ 50 , 110 ]. The last challenge facing the advancement of CAR-NKT cell therapy is persistence duration in TME.…”

“…One of the other solutions to improving cancer treatment is the enhancement function of NKT cells in TME and better recognition of Th1-based lipid antigens [ 110 ]. For example, IL-15 co-expression in CAR-NKT cells increases their localization at the tumor site and improves tumor control without any toxic effects.…”