Biology subjects

Raulet, D. H.

Publications and source records attributed to Raulet, D. H..

4 recordsLinked to original sources

bioRxiv2026

ITPKB is a conserved regulator of natural killer cell desensitization/education that constrains antitumor immunity

Natural Killer (NK) cell desensitization induced by persistent stimulation limits durable antitumor immunity, yet the molecular mechanisms governing this dysfunctional state remain poorly defined. To identify conserved regulators of NK cell desensitization, we performed comparative transcriptomic analyses across multiple murine models of persistent activation and dysfunction. This approach defined a shared transcriptional program of desensitization and identified Itpkb to be upregulated across multiple distinct contexts. Genetic and pharmacological inhibition of ITPKB enhanced degranulation, cytokine production, and cytotoxicity in both murine and human NK cells under multiple desensitization settings. Mechanistically, ITPKB regulated signaling downstream of persistent activation through the IP3/IP4 axis, limiting calcium mobilization and NFAT-dependent transcriptional responses in desensitized NK cells. Furthermore, inhibition or deletion of ITPKB enhanced NK-cell mediated tumor control in vivo and improved the efficacy of adoptively transferred CAR-NK cells, underscoring the translational potential of targeting this pathway. Together, these findings identify ITPKB as a cell-intrinsic regulator of NK cell desensitization and support targeting the IP3/IP4 signaling axis to enhance NK cell-mediated antitumor immunity.

immunology↗

bioRxiv2026

Viral capsid delivery of cGAMP enhances STING-dependent antitumor immune response

Therapies to activate the STING immune response pathway represent promising potential anticancer treatments. However, the native STING activating molecule, 2,3-cGAMP, is a poor drug candidate due to its susceptibility to nuclease degradation and its relatively poor cell uptake. In this study, we present a nanoscale delivery vehicle based on the bacteriophage MS2 virus-like particle that can both protect cGAMP and deliver it into cells to access and bind cytosolic STING. MS2-delivered cGAMP achieved greatly increased STING activation potency relative to both free cGAMP and a nuclease-resistant synthetic cGAMP analog. In an in vivo murine colon carcinoma model, MS2-cGAMP elicited significant and prolonged antitumor activity in a STING-dependent manner at 50-fold lower concentrations relative to free cGAMP and synthetic analogs. These results demonstrate that MS2 delivery of cGAMP can yield a highly potent STING agonist immunotherapy with in vivo anticancer activity.

immunology↗

bioRxiv2022

STING activation depends on ACBD3 and other phosphatidylinositol 4-phosphate-regulating proteins

STING induces transcription of pro-inflammatory genes upon activation at the Golgi apparatus. Many of the regulators involved in STING activation are unknown. We found that ACBD3 and other phosphatidylinositol 4-phosohate (PI4P) regulating proteins play a critical role in STING activation. We show that proper STING localization and activation at the Golgi depended on ACBD3 and PI4KB expression. Furthermore, depleting PI4P by inactivating PI4KB or overexpressing Sac1 diminished STING activation. STING signalling was also regulated by the lipid-shuttling protein OSBP, which removes PI4P from the Golgi. OSBP inhibition by the FDA-approved antifungal itraconazole and other OSBP inhibitors greatly enhanced STING activation by increasing the levels of STING-activating phospholipids. Itraconazole-enhanced STING activation resulted in a hundred to thousand-fold increased expression of interferon-beta and other cytokines. In conclusion, the phospholipid PI4P is critical for STING activation and manipulating PI4P levels is a promising therapeutic strategy to alter the STING immune response.

immunology↗

bioRxiv2021

Powerful synergistic effects of a STING agonist and an IL-2 superkine in cancer immunotherapy against MHC I-deficient and MHC I+ tumors

Cyclic dinucleotides (CDNs) and TLR ligands mobilize antitumor responses by NK cells and T cells, potentially serving as complementary therapies to immune checkpoint therapy. In the clinic thus far, however, CDN therapy has yielded mixed results, perhaps because it initiates responses potently, but does not provide signals to sustain activation and proliferation of activated cytotoxic lymphocytes. To improve efficacy, we combined CDNs with a half-life extended IL-2 superkine, H9-MSA. CDN/H9-MSA therapy induced dramatic long-term remissions of the most difficult-to-treat MHC I-deficient and MHC I+ tumor transplant models. H9-MSA combined with CpG oligonucleotide also induced potent responses. Mechanistically, tumor elimination required CD8 T cells and not NK cells in the case of MHC I+ tumors and NK cells but not CD8 T cells in the case of MHC-deficient tumors. Furthermore, combination therapy resulted in more prolonged and more intense NK cell activation, cytotoxicity and expression of cytotoxic effector molecules in comparison to monotherapy. Remarkably, in a primary autochthonous sarcoma model that is refractory to PD-1 checkpoint therapy, the combination of CDN/H9-MSA combined with checkpoint therapy yielded long-term remissions in the majority of animals, mediated by T cells and NK cells. This novel combination therapy has potential to activate responses in tumors resistant to current therapies and prevent MHC I-loss accompanying acquired resistance of tumors to checkpoint therapy. One sentence summaryPowerful immunotherapy effects mediated by the combination of innate agonists and superkine.

immunology↗