Chemotherapy induced immunogenic cell death alters response to exogenous activation of STING pathway and PD-L1 immune checkpoint blockade in a syngeneic murine model of ovarian cancer
Bibliographic record
Abstract
Abstract Poor response to platinum/taxane-based chemotherapy has remained a major hurdle in the management of high grade serous carcinoma of the ovary (HGSC). Recurrent HGSC is often treated with liposomal doxorubicin as a second line chemotherapy. Unfortunately, HGSC patients have not benefited from immunotherapies targeting the PD-1/PD-L1 immune checkpoint axis. In a pre-clinical study evaluating the efficacy of a “Stimulator of Interferon Genes” (STING) agonist, we demonstrated the synergistic potential of STING pathway activation in enhancing response to carboplatin chemotherapy and sensitization to PD-1 immune checkpoint blockade (ICB). Since carboplatin and doxorubicin exhibit distinct immunogenic cell death (ICD) inducing potential, we investigated the chemotherapy specific effect in the magnitude of response to exogenous STING pathway activation. Immunocompetent C57/BL6 mice were implanted with ID8- Trp53 −/− cells followed by treatment with carboplatin or doxorubicin. Towards rationalized addition of STING agonist with or without PD-L1 blockade, we first determined the expression of 60 known ICD associated genes at an early time point following the initial treatment with carboplatin or doxorubicin with or without STING agonist. Doxorubicin treated tumours showed significantly higher expression of ICD genes, Cxcl10, Cd274, Isg15, Psmb9 and Calr . Expression changes were further amplified following the addition of STING agonist. Significantly higher expression of Cxcl10 and Isg15 were observed in the doxorubicin + STING agonist treated mice compared to carboplatin + STING agonist combination. Interestingly, Ccl5 gene expression was higher in the tumours from carboplatin or carboplatin and STING agonist combination treated mice compared to those treated with doxorubicin. Plasma cytokine analysis showed distinct profiles of CXCL10, CCL5, MCP-1 and IL6 post treatment with each chemotherapy type. Doxorubicin monotherapy treated mice showed significantly longer overall survival compared to their carboplatin counterparts with further increases following addition of either STING agonist or PD-L1 ICB. However, despite the stronger ICD inducing ability of doxorubicin, overall survival of mice treated with carboplatin + STING agonist + PD-L1 ICB was the longest. Findings from our pre-clinical study provide novel insights for rationalized combinations of immune sensitizing agents such as STING pathway activators to improve response of HGSC patients to chemotherapy and ICB in the primary and recurrent settings.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
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".