Abstract 3445: Immune cells infiltration and activation are higher in breast cancers resistant to antiestrogen therapy
Bibliographic record
Abstract
Abstract We investigated the tumor microenvironment (TME) in estrogen receptor positive (ER+) primary breast cancers from stage I-III patients treated with estrogen deprivation (ED, induced with letrozole) for 10-21 days. We used primary breast cancer biopsies, collected from 198 patients, to assess tumor-infiltrating lymphocytes (TILs), transcriptomic profiles, and TME composition. Diagnostic biopsy and surgical on-treatment tumor specimens were collected; Ki67, ERα, PR, and HER2 expression were measured using automated quantitative analysis (AQUA). Tumors were categorized as estrogen deprivation-sensitive (ED-S) or -resistant (ED-R) based on the natural log (ln) of the Ki67 score (ln ≤1.0 or ≤2.7% Ki67+ cells vs. ln ≥2.0 or ≥7.4%, respectively) in the on-treatment (surgical) biopsy. Scoring of stromal (s)TILs, using hematoxylin and eosin staining of on-treatment specimens, revealed that sTILs were elevated in ED-R compared to ED-S tumors (p<0.0001). We next constructed tissue microarrays (TMAs) of on-treatment tumor sections and performed cyclic immunofluorescence (CyCIF) with 38 antibodies, including markers of hormone receptors, immune cells, signaling pathways, proliferation, DAPI (nuclei), and others. We then segmented single cells from each tumor core and designated them as immune, cancer, or stromal cells based on expression of a set of markers. Briefly, cells that stained strongly for CD45 (leukocyte marker), and/or CD4 (T lymphocyte marker), or CD68 (macrophage marker) were considered immune cells. CD45/CD4/CD68-negative cells were categorized as tumor, if E-cadherin and/or cytokeratin-positive, or stromal cells, if -negative. To investigate the TME composition, we next assessed cell specific spatial enrichment by quantifying the expression of immune markers in the area immediately adjacent to each tumor cell. Relative to ED-S, ED-R samples exhibited higher CD45+ cells (p<0.0001) and higher CD8+ T cells (p=0.0329), while CD4+ T cells showed no difference. Conversely, immune-suppressive T-reg (CD4+FOXP3+) cells were enriched in the ED-S samples (p=0.0004). In addition, PD1, a marker for T cell exhaustion, was higher in the ED-S group (p=0.0004), as were CD68+ cells (p<0.0001). To confirm and expand upon these findings, RNA-sequencing was performed on the on-treatment tumor sections. Gene set enrichment analysis of hallmark gene signatures revealed that immune-related gene sets, such as “IFNα response”, “IFNɣ response”, “allograft rejection”, and “inflammatory response” were enriched in ED-R vs. ED-S tumors. In summary, our study shows that activated anti-tumor immune cells are enriched in the TME of ER+ breast tumors resistant to estrogen deprivation, whereas ED-sensitive tumors show a more immunosuppressed or immune cold milieu. These data suggest a potential causal link between antiestrogen treatment and modulation of antitumor immunity in ER+ breast cancers. Citation Format: Fabiana Napolitano, Dhivya R. Sudhan, Yunguan Wang, Paula I. González-Ericsson, Luigi Formisano, Kyung-Min Lee, Chang-Ching Lin, María Rosario Chica-Parrado, Hongli Ma, Nathaniel Evans, Alberto Servetto, Saurabh Mendiratta, Spencer Barnes, Yisheng V. Fang, Justin M. Balko, Gordon B. Mills, Marilyne Labrie, Ariella B. Hanker, Carlos L. Arteaga. Immune cells infiltration and activation are higher in breast cancers resistant to antiestrogen therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3445.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 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".