Aryl Hydrocarbon Receptor Inhibition Activates Mito-calcium/mtROS/IL-12 Axis in Dendritic Cells to Promote Tumor Suppression — ASN Events
  1. Schedule
  2. Parallel Symposium B: DC Metabolism and Cellular Programming of Function & Fate
  3. Aryl Hydrocarbon Receptor Inhibition Activates Mito-calcium/mtROS/IL-12 Axis in Dendritic Cells to Promote Tumor Suppression

Aryl Hydrocarbon Receptor Inhibition Activates Mito-calcium/mtROS/IL-12 Axis in Dendritic Cells to Promote Tumor Suppression (#169)

Mridula Prakash Menon 1 , Chen-Yun Yeh 1 , Yi-Jun Lan 1 , Yu-Chi Huang 1 , Joaquin Antonio B. Limbo 1 , Ching-Hui Tsai 1 , Francisco J. Quintana 2 3 , Tsen-Fang Tsai 4 , Steven Lin 5 , Peilin Chen 6 , Yungling Leo Lee 1
  1. Institute of Biomedical Sciences, Academia Sinica, 128 Sec. 2, Academia Road, Nankang , Taipei 115, Taiwan R.O.C
  2. Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
  3. Broad Institute of MIT and Harvard, Cambridge, MA, USA
  4. Department of Dermatology, National Taiwan University Hospital, Zhongzheng District, Taipei 115, Taiwan
  5. Institute of Biological Chemistry, Academia Sinica, 128 Sec. 2, Academia Rd. Nankang, , Taipei 115, Taiwan, R.O.C.
  6. Research Center for Applied Sciences, Academia Sinica, 128 Sec. 2, Academia Rd. Nankang, Taipei 115, Taiwan R.O.C.

IL-12 generated by dendritic cells (DCs) plays a pivotal role in activating an effective anti-tumor response. Specific genetic manipulation of DCs to enhance tumor infiltration and localized IL-12 secretion is an attractive therapeutic strategy for cancer immunotherapy.

            Using genome-wide CRISPR/Cas9 screening in bone marrow-derived DCs, we identified aryl hydrocarbon receptor (AhR) as the key negative regulator of IL-12 production. AhR activation is positively correlated with tumor progression in the MC38 syngeneic tumor model. DC-specific AhR knockout reduces tumor growth by promoting infiltration of IL-12+ CD11c+ MHCII+ DCs and CD69+ CD107a+ NK1.1+ cells during early MC38 growth. Neutralizing IL-12 in these tumor-bearing mice diminishes tumor suppression. Functional antibody blockade of immune cells in MC38-implanted AhR∆DC mice highlights NK cells as the primary effector in mediating tumor suppression. Using 3-dimensional two-photon intravital imaging, we found that AhR inhibition augmented NK migration, extravasation, and interaction with IL-12+ cells in the TME.

            Bulk RNA sequencing of early-stage TIDCs revealed an upregulation of mitochondrial biogenesis genes in the absence of AhR. These DCs also exhibited higher mtROS production while preserving mitochondrial structure and membrane potential. Furthermore, AhR knockout increased TLR4 signaling and enriched mitochondria-ER contacts (MERCs), leading to IP3R/VDAC1/MCU-mediated mitochondrial calcium influx, elevated mtROS, and IL-12 production in DCs. AhR inhibition in human DCs enhanced tumor-killing function in NK cells in an mtROS- and IL-12-dependent manner. In conclusion, we demonstrate that AhR ablation in DCs releases the inhibitory brake on the IP3R-gated mito-calcium/mtROS/IL-12 axis. This facilitates DC-NK infiltration and crosstalk within the TME. Our study provides new insights into how AhR keeps DCs in an immune-nonresponsive state by blocking IL-12 production to support tumor growth. We emphasize the importance of mtROS and mitochondria-ER dynamics as potential targets for enhancing DC function in cancer immunotherapy.