Abstract B78: Improving chemotherapy response of immunologically cold high-grade serous ovarian cancer with loss of PTEN using STING agonist
Bibliographic record
Abstract
Abstract High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy, with high rates of chemotherapy resistance and poor outcomes. We previously showed that tumors from chemotherapy-resistant patients show an immunologically cold phenotype, exhibiting lower density of CD8+ T cells and low expression of interferon genes. Subsequently, using the ID8-Trp53−/− murine model of HGSC, we further demonstrated the potential of Stimulator of Interferon Genes (STING) pathway activation in enhancing response of HGSC to carboplatin chemotherapy. Currently, we aim to better characterize the effect of cancer cell genotype on response to treatment in HGSC. The evolution of the tumor immune microenvironment (TIME) as immunologically hot or cold can be to some extent dictated by cancer cell-specific genetic alterations. While loss of the tumor suppressor TP53 is a universal mutation (>96% of cases), previous reports in HGSC have shown that patients with BRCA1 mutations (~25% of cases) have higher CD8+ T-cell infiltration and higher chemosensitivity. In contrast, loss of PTEN (seen in ~20% of cases) is associated with poor outcomes and chemoresistance. We hypothesized that HGSC tumors with loss of PTEN expression can benefit via immunomodulatory treatment approaches that activate the STING pathway following chemotherapy. C57/BL6 mice were implanted with either ID8-Trp53−/−; Brca1−/− cells or ID8-Trp53−/−; Pten−/− cells and subjected to one of three treatment groups: vehicle, carboplatin, or carboplatin + STING agonist. Characterization of the TIME generated from ID8-Trp53−/−; Brca1−/− cells, and those from ID8-Trp53−/−; Pten−/− cells, through local and systemic immune profiling, showed significant immunologic differences between different genotypes. Addition of STING agonist significantly increased chemosensitivity and improved overall response in ID8-Trp53−/−; Pten−/− injected mice compared to those treated with carboplatin alone. This study helps to determine the potential of STING pathway activation in inducing an activated tumor immune state in genotypes of HGSC that result in a “cold” TIME, such as loss of PTEN, to augment responses to chemotherapy and prolong survival. Citation Format: Noor Shakfa, Elizabeth Lightbody, Afrakoma Afriyie-Asante, Vinicius Kannen, Madhuri Koti. Improving chemotherapy response of immunologically cold high-grade serous ovarian cancer with loss of PTEN using STING agonist [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B78.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.002 | 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".