Abstract A012: STING agonists drive intrinsic type I interferon responses in monocytes for optimal anti-tumor immunity
Bibliographic record
Abstract
Abstract The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is triggered by the sensing of cytosolic DNA, triggering the production of type I interferon (IFN-I) and play a crucial role in host defense against pathogens. This pathway also induces an anti-tumor response when tumor-derived DNA is sensed. Small molecule agonists called STING agonists activate this pathway and have been shown to cause tumor regression in mice. However, it is unclear how immune cells respond to STING agonist-induced IFN-I. In our study, we observed that monocytes were abundantly recruited to tumors during STING agonist therapy, and the lack of CCR2+ Ly6Chi inflammatory monocytes in CCR2-knockout (KO) mice led to impaired responses to STING agonist therapy of B16F10 and MC-38 tumors. Single-cell RNA sequencing (scRNA-Seq) of CD45+ cells from lymph nodes and tumors of Ifnar1 mixed bone marrow chimeric mice in which half of the immune cells lacked IFN-I receptors revealed that inflammatory monocytes upregulated chemokine receptor ccr5 and genes associated with MHC-I restricted antigen presentation in response to IFN-I. Using mice with B16.OVA.Tomato red fluorescent tumors, we demonstrated that IFN-I-responsive monocytes captured fluorescent antigens in tumors and transported them to lymph nodes. Additionally, the administration of CCR5 antagonist, maraviroc, significantly reduced the number of fluorescent antigen-carrying monocytes in the lymph nodes of red fluorescent tumor-bearing mice treated with STING agonists, indicating the involvement of CCR5 in monocyte-mediated antigen transport. Furthermore, NicheNet analysis of scRNA-Seq data showed that IL-18 - IL-18R1 interaction was the top predicted interaction between inflammatory monocytes and CD8+ T cells or NK cells. Blocking IL-18 remarkedly reduced the therapeutic efficacy of STING agonist treatment. Moreover, IFN-I acted on monocytes to upregulate glucocorticoid-induced TNFR-related (GITRL) providing a pro-survival signal to T cells. Deletion of GITRL on CCR2+ monocytes led to impaired tumor control, and the absence of the cognate receptor GITR on T cells led to impaired anti-tumor effector T cell responses in the tumors treated with and tissue-resident memory T cell accumulation in the skins that rejected tumors with STING agonist therapy. Taken together, our data suggests that STING agonists induce IFN-I-responsive monocytes to promote anti-tumor responses through secreting IL-18, potentially through transporting antigens to lymph nodes, and through providing a pro-survival signal for T cell accumulation in the tumors during STING agonist therapy. Citation Format: Tianning Yu, Melanie Girard, Tania H Watts. STING agonists drive intrinsic type I interferon responses in monocytes for optimal anti-tumor immunity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A012.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".