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Spatial transcriptomic analysis of 53 pre-treatment biopsies from LARC patients using GeoMx technology

ABSTRACT: Locally Advanced Rectal cancer (LARC) is treated using neoadjuvant chemoradiotherapy (nCRT) followed by surgery. On average 15% of tumors at surgery will present a pathological complete response (pCR). Increasing pCR can be done at the cost of treatment intensification usually combining nCRT and chemotherapy which comes with higher toxicity. However, many LARC patients do not respond to the current neoadjuvant treatments while experiencing important treatment related side effects. Predicting pCR following nCRT opens the door to non-surgical management - the watch and wait strategy and avoid escalation as well as sparring non-responders from nCRT in patients not eligible for intensification. Using RNA expression data, several groups have defined predictive signatures, however, none have made it into clinical practice. A comprehensive differential expression analysis was conducted across six Gene Expression Omnibus (GEO) datasets, followed by integration with four microarray datasets for refinement. A machine learning approach was employed to identify a 186-gene signature predictive of response to nCRT, validated using cross-validation. Gene set enrichment analysis (GSEA) was performed to explore biological pathways associated with treatment response. Spatial transcriptomic profiling of pre-treatment biopsies further examined gene expression in tumor and stroma compartments and identified eight compartment-specific genes significantly associated with response, with tumor-associated genes showing greater predictive value than stroma-associated genes. This study identifies a novel 186-gene signature associated with nCRT response in LARC, with potential clinical utility in guiding personalized treatment. Further validation in larger cohorts and exploration of spatial biomarkers are needed to confirm its clinical relevance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE279942 | GEO | 2025/09/25

REPOSITORIES: GEO

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Project description:Background: Neoadjuvant chemoradiotherapy (NCRT) is the treatment of choice in advanced rectal cancer, even though there are many patients who will not benefit from it. There are still no effective methods for predicting which patients will respond or not. The present study aimed to define the genomic profile of rectal tumors and to identify alterations that are predictive of response in order to optimize therapeutic strategies. Methods: Forty-eight candidates for NCRT were recruited and their pretherapy biopsies analyzed by array Comparative Genomic Hybridization (aCGH). Pathologic response was evaluated by tumor regression grade (TRG).Results: Both Smoothing and Hidden Markov Model (HMM) approaches identified similar alterations, with a prevalence of DNA gains. Non responsive patients had a different alteration profile from responsive ones, with a higher number of genome changes mainly located on 2q21, 7q21, 7q36, 13q12, 13q32-34, 16p13, 17p12 chromosomal regions. Conclusion: This exploratory study suggests that an in depth characterization of chromosomal alterations by aCGH would provide useful predictive information about response to NCRT and help to optimize therapy in rectal cancer patients. 48 samples included in the study were analyzed on whole genome BAC arrays with the aim to characterize genomic alterations and correlate them with the tumor response to therapy. The case series was composed by 15%,81% and 4% of uT2, uT3 and uT4 tumors, respectively. At the diagnosis 56% of patients had uN0 tumors and 44% uN+. 30%,13%, 23% and 34% of patients reached/mantained respectively ypT0, ypT1, ypT2 and ypT3. With regard to response to NCRT, according to TRG criteria proposed by Dworak, two group were defined: non responders (TRG0-2= 56%) and responders (TRG3-4=44%). Clinical and pathological parameters: uT: pre-therapy stage determined by ultrasounds techniques uN: pre-therapy lymph node status determined by ultrasounds techniques ypT: pathologic stage after a neoadjuvant treatment ypN: pathologic lymph node status after a neoadjuvant treatment

Project description:Introduction: Neoadjuvant chemoradiotherapy (nCRT) was the foundation treatment for locally advanced rectal cancer (LARC). The nCRT can improve the efficacy of immunotherapy on account of its in-situ vaccine effect. Objective: The aim is to identify stable and reliable transcriptome signatures to predict the efficacy of immune checkpoint blockade (ICB) in patients with LARC. Methods: Immunophenotyping was established by using xCell immune cell infiltration abundance and consistent clustering in GSE39582 and verified in several data sets. The effects of immunophenotyping, follicular regulatory T cells, tumor associated fibroblasts (CAF) and tertiary lymphoid structures (TLS) signatures on the efficacy of ICB were analyzed by using IMvigor210, GSE91061 and an independent Daping Hospital (DPH) cohort. Results: There are four stable and repeatable immune subtypes in rectal cancer, among which C1 is low immune infiltration type, C2 is high interstitial infiltration type, C3 is high immune infiltration type and C4 is ion channel type. C2 is mainly characterized by high infiltration CAF, C3 is characterized by high infiltration of cytotoxic T lymphocytes, high expression of PD-L1 and TLS. In rectal cancer patients receiving nCRT, immunophenotyping was not significantly associated with pathological remission rate, but immunophenotyping was an independent prognostic factor of RFS. In IMvigor210 patients treatment with atezolizumab, the pathological remission rates of C1, C2, C3 and C4 were 23.86%, 10.94%, 33.33% and 23.08% respectively (χ2 = 8.981, P = 0.029), which were 11.76%, 50.00%, 42.86% and 0.0% respectively in the GSE91061 patients treatment with nivolumab (Fisher's exact probability, P = 0.018). Both follicular regulatory T cells and CAF showed a further impact on the ICB therapeutic efficacy of C2 and C3 subtype. In addition, both GSE91404 and DPH cohorts showed that nCRT treatment induced a significant increase in the expression of TNFRSF9 and abundance of macrophages in C3 subtype. Conclusion: Our data suggest that there are four immune types of rectal cancer, which are related to the prognosis of patients. Among them, C3 and some C2 subtypes represents the patients who may benefit from ICB after nCRT treatment.

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Spatial transcriptomic analysis of 53 pre-treatment biopsies from LARC patients using GeoMx technology

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