Integrative analysis of tumor microenvironment in advanced pancreatic cancer: Unraveling genomic and immune landscape for targeted therapies.
Bibliographic record
Abstract
4182 Background: An understanding of genotype and immunophenotype interactions in advanced pancreatic ductal adenocarcinoma (PDAC) is important in designing combination strategies. In addition, PDAC subtypes may harbor unique tumor immune microenvironments (TMEs) and confer differential sensitivity to KRAS inhibitors (KRASi). We aimed to characterize the baseline TME in advanced PDAC and its relationship with genomic, transcriptomic and clinical data. Methods: The COMPASS trial (NCT02750657) investigated whole genome (WGS) and transcriptome (RNA-Seq) sequencing in patients (pts) receiving first line therapy for advanced PDAC. We performed multiplex immunohistochemistry (mIHC) to identify 5 immune cell subtypes (CD8+/CD4+ T cells, Tregs, B cells and macrophages) and CIBERSORT, a deconvolution method that uses gene expression profiles. Statistical analyses were performed using STATA/R software and significance was defined as p - value < 0.05. Multivariate logistic regression was used and Kaplan Meier analyses evaluated impact on survival. Results: Of 268 pts, 62 had available tissue samples with mIHC, WGS, and RNA-Seq data (n = 21 primary biopsies, n = 41 metastases, 34/41 liver). All 62 pts had KRAS mutations (28 G12D, 19 G12V, 10 G12R, 5 other) and 29 had KRAS major or minor imbalances. 55 cases (88.7%) were classified as classical subtype and HRDetect hi was seen in 10 pts, including 5 with BRCA1/2 mutations (4 germline, 1 somatic). In the overall cohort, differences between tumor and stroma were evident with increased infiltration of CD8 and CD4 Tcells and Tregs in stroma ( p < 0.001) and increased macrophages (p= 0.0343) in tumor. CIBERSORT in a subset of 51 pts demonstrated increased M0 (p= 0.0035) and M2 macrophages ( p = 0.0067) in liver metastases compared to primary samples, suggesting a more immunosuppressive TME. A higher number of B cells were seen in lung metastases (median 207.5 vs. 43.2 vs. 3.7 vs. 1.8 cells/mm2, p = 0.011) compared to abdominal wall, peritoneum and liver, respectively. Pts with KRAS major imbalance (n =14, 3 basal like) were found to have higher median numbers of CD8+ (114.5 vs. 25.1 vs. 27.5 cells/mm2, p = 0.038) and CD4+ Tcells (292.1 vs 133.4 vs. 97.4 cells/mm2, p = 0.005) when compared to minor/balanced samples, respectively. Basal-like PDAC had fewer macrophages than classical subtype (median 13.2 vs. 28.2 cells/mm2, p = 0.0103). On survival analysis, pts with HRDetect lo and classical subtype with higher macrophage counts had a tendency towards increased survival (median OS: 11.8 vs. 9.5 months, p = 0.066). Conclusions: We identified increased CD8/CD4 T cell infiltration in PDAC stroma, as well as in pts with KRAS major imbalance. Immune cell profiling may complement molecular profiling as potential biomarkers and warrants further study in this context.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".