Abstract PR009: Bugs in Space: Spatial Analysis of the Immune-Microbial Axis in Rectal Cancer Reveals a Unique Interface in Young Onset Rectal Cancers
Bibliographic record
Abstract
Abstract Several hypotheses have been postulated to define the mechanism behind the rising incidence of young onset rectal cancer (YORC). These hypotheses often relate to differences in a population’s exposome and back to a patient’s gut or tumor microbiome. We previously demonstrated a unique tumoral microbiome in YORC (<50 years old) versus late-onset (≥50 years old, LORC) rectal cancers through metagenomic quantification of intra-tumoral bacteria. Here we further compare tumoral immune signatures in response to the presence of tumoral bacteria between YORC and LORC. We build on previous bulk sequencing analyses to correlate tumoral microbial presence with rectal cancer outcomes and tumor immune infiltrates with the hypothesis that tumoral bacteria lead to derangements in local host immune response as a mechanism to affect response rates to neoadjuvant therapy. Pretreatment biopsies from rectal adenocarcinomas were studied using NanoString GeoMx digital spatial profiling using the Whole Human Transcriptome Atlas and 16S rRNA probes. We initially studied the impact of bacterial presence in these tumors and noted distinct immune profiles when comparing sterile (Baclow) with bacterially enriched (Bachigh) regions of the tumor. In Bachigh regions, a higher proportion of memory B-cells (p=0.042) and M1 macrophages (p=0.023) and lower abundance of naïve B cells (p=0.046) were noted – suggesting a decrease in adaptive immunity in Bachigh regions of the tumor. Importantly lower bacterial density and increased B cell activity each correlated with higher rates of pathologic response. Differential expression of genes previously associated with deleterious microbes and tumor progression such as CXCL8 (p<0.001), VIM (p=0.010), TGFBI (p=0.004), and SPP1 (p=0.018) were noted in Bachigh tumor regions. While CXCL8 (p=0.046), MYC (p=0.024), VEGFA (p=0.008), and ICAM1 (p=0.005) were upregulated in Bachigh stromal regions. This underscores the important role tumoral bacteria play in rectal cancer derangement of the host immune response and the associated evasion of tumor response to cytotoxic neoadjuvant therapy resulting in poorly controlled progression of these tumors. When comparing the effect of bacteria on these immune infiltrates in YORC and LORC, we see B cell maturation suppressed in the Bachigh regions of YORC with a decrease in memory B cell populations (p=0.005) and a concomitant increase in naïve B cells (p=0.004). While LORC Bachigh regions were associated with an immune landscape skewed toward innate inactivation and an increase in neutrophils (p=0.091), dendritic cells (p=0.011), and inactivated NK cells (p=0.026) and an increase in extracellular matrix (ECM) organization, proteoglycans, and degradation. Ongoing studies will confirm whether this differential response between YORC and LORC patients is secondary to age, specific bacterial populations, or a combination of factors. Ultimately, however, these bacteria provide intriguing targets for clearance as being studied (NCT06569368) during neoadjuvant therapy for locally advanced rectal cancers. Citation Format: Ryan Morgan, Reed Ayabe, Brenda Melendez, Taylor Neilson, Laurence Diggs, Norman Galbraith, Ashish Damania, Bharat Singh, Matthew Wong, Pranoti Sahasrabhojane, Yasmine Hoballah, Melissa Taggart, Alexander Lazar, Khalida Wani, Davis Ingram, Diana Shamsutdinova, Jumanah Alshenaifi, Zuzana Lutter-Berka, David Menter, Ramy Behman, Paula M. Smith, George J. Chang, Nadim Ajami, Susan Bullman, Christopher Johnston, Scott Kopetz, J. Joshua. Smith, Jennifer A. Wargo, Y. Nancy. You, Michael G. White. Bugs in Space: Spatial Analysis of the Immune-Microbial Axis in Rectal Cancer Reveals a Unique Interface in Young Onset Rectal Cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl):Abstract nr PR009.
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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 | 0.003 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.003 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| 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".