Abstract B041: Defining the Determinants of Immune Response in DNA Homologous Recombination Deficient Tumors
Bibliographic record
Abstract
Abstract Immune checkpoint blockade (ICB) has shown unprecedented success in improving clinical outcomes for numerous cancer patients, but many patients still fail to respond to treatment. Studies have demonstrated that the tumor microenvironment, tumor mutational burden, and patient DNA Damage Repair (DDR) deficiency may play a key role in determining response to ICB. To better characterize this and define key determinants of ICB response, we created an isogenic knockout BRCA2 in a murine 4T1 metastatic TNBC background to model these differential clinical responses and to assess how these tumor-intrinsic programs influence the tumor immune microenvironment to poise tumors for immunotherapy response. Differential immune landscapes were found via scRNAseq at baseline and with ICB driven by tumor DDR status with notable differences in the myeloid compartment and CXCR3-expressing T cell, NK, pDC, DCs, and plasma cells. Differential expression and interferon stimulated gene (ISG) metagene analysis showed notable differences in ISG expression in DDR-deficient samples at baseline, particularly in clusters containing monocytes and macrophages. Additionally, differential expression of CXCL10 in monocytes/macrophages and assessment of ligand-receptor interactions by CellChat similarly showed enhanced contribution CXCL10-CXCR3. Parallel bulk RNAseq analysis showed increased production of T cell trafficking chemokines that would poise the tumor for response to ICB. Our lab established a genetic interferon reporter system to measure both tumor intrinsic interferon-driven inflammation in cis and in trans with tumor associated macrophages, which enables multidimensional tracking of bidirectional signaling between tumor cells and macrophages by flow. This system enabled screening of inhibitors and tumor knockout cell lines to identify that tumor-intrinsic cGAS/STING and IFNb1 reinforce production of tumor and myeloid CXCL10/11 to poise the tumor for response to ICB. Further assessment of tumor cell lines via cellular fractionation experiments identified the presence of both gDNA and R-loops in the cytoplasm of BRCA2-mutant mammary cancer cell lines that may be detected as damage associated molecular patterns by tumor cells or myeloid cells in the tumor bed. Future studies aim at validating this DDR-driven production of IFNb1 as a driver of T cell chemokines in vivo; tumor-intrinsic knockout of IFNb1 and other T cell promoting chemokines (CXCL10/11/CCL5) to assess tumor or myeloid driven nature of this response to ICB and depletion of myeloid cells are being performed in parallel to assess contribution of tumor and myeloid cells, respectively. Taken together, our results have important implications for understanding the key drivers of ICB response in the tumor microenvironment and how patient-intrinsic mutations differentially poise the microenvironment for immunotherapy response. Citation Format: Natalie Vaninov, Robert Samstein. Defining the Determinants of Immune Response in DNA Homologous Recombination Deficient Tumors [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 B041.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.006 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".