Ill Fate of Rectal Mucinous Adenocarcinoma: A Defect in Immunosurveillance or a Mucin Coating Effect?-The IMMUNOREACT 20 Study.
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Dell'Atti Lorenzo, Kotsafti Andromachi, Galuppini Francesca, Scarpa Melania, Salmaso Roberta, Stepanyan Astghik, Sbaraglia Marta, Saadeh Luca Maria, Tussardi Gaia, Rosato Antonio, Angriman Imerio, Ruffolo Cesare, Urso Emanuele Damiano Luca, Bao Quoc Riccardo, Negro Silvia, Maretto Isacco, Facci Luca, Rivella Giorgio, D'Angelo Antonella, Matteazzi Anna, Vignotto Chiara, Baldo Andrea, Guzzardo Vincenza, Pellegrini Valerio, Brignola Stefano, Ceccon Carlotta, Stecca Tommaso, Pozza Anna, Massani Marco, De Simoni Ottavia, Pilati Pierluigi, Gruppo Mario, Franzato Boris, Cataldo Ivana, Portale Giuseppe, Cipollari Chiara, Zuin Matteo, Laurino Licia, Dal Santo Luca, Pirozzolo Giovanni, Recordare Alfonso, Ceccarini Lavinia, Antoniutti Michele, Marinelli Laura, Brolese Alberto, Barbareschi Mattia, Bertalot Giovanni, Ortenzi Monica, Guerrieri Mario, Zizzo Maurizio, Fabozzi Massimiliano, Guerriero Silvio, Piccioli Alessandra, Pozza Giulia, Godina Mario, Mondi Isabella, Verdi Daunia, Da Lio Corrado, Noaro Giulia, Cola Roberto, Bordignon Giovanni, Merenda Roberto, Becherucci Giulia, Gavagna Laura, Candioli Salvatore, Tagliente Giovanni, Tedeschi Umberto, Parini Dario, Salmaso Beatrice, Businello Gianluca, Cristofaro Loretta Di, Marchegiani Francesco, Bergamo Francesca, Lonardi Sara, Porzionato Andrea, Chiminazzo Valentina, Scognamiglio Federico, Bardini Romeo, Pucciarelli Salvatore, Agostini Marco, Gregori Dario, Di Camillo Barbara, Castagliuolo Ignazio, Spolverato Gaya, Fassan Matteo, Dei Tos Angelo Paolo, Scarpa Marco
Аннотация
METHODS: Two hundred patients with rectal adenocarcinoma (16 MAC, 184 NOS-AC) from the IMMUNOREACT 1 (NCT04915326) and IMMUNOREACT 2 (NCT04917263) prospective cohorts were included. To account for the imbalance in baseline characteristics, propensity score matching (PSM) was performed on age, sex, neoadjuvant treatment and TNM stage. The immune microenvironment was characterised using immunohistochemistry (CD3, CD4, CD8, CD8β, Tbet, FoxP3, PD-L1, MSH6, PMS2, CD80), flow cytometry and NanoString PanCancer IO 360™ transcriptomics of adjacent healthy mucosa. Findings were externally validated against TCGA rectal and colon adenocarcinoma datasets.
RESULTS: MAC presented at significantly more advanced stage than NOS-AC across all TNM parameters: higher T stage (p = 0.006), N stage (p < 0.001), M stage (p = 0.039) and overall TNM stage (p < 0.001). In the unmatched cohort, MAC was associated with worse overall survival (HR 2.53; 95% CI 1.03-6.23; p = 0.043) and disease-free survival (HR 2.86; 95% CI 1.25-6.55; p = 0.013), but both differences became non-significant after PSM. MAC patients had higher haemoglobin after adjusting for confounders (mean difference [MD] 1.26 g/dL, 95% CI 0.30-2.31, p = 0.012), consistent with a hypothesis of reduced chronic rectal bleeding as a possible mechanism for late presentation. Transcriptomically, MAC showed suppression of HLA class II antigen presentation genes (HLA-DQA1, HLA-DQB1, HLA-DRB1) and myeloid activation genes (S100A8/A9/A12) in adjacent healthy mucosa. Loss of MMR proteins MSH6 and PMS2 in histologically normal mucosa was significantly more frequent in MAC. These findings were replicated in the TCGA cohort, which also showed lower tumour mutational burden and a distinct mucin-associated transcriptomic profile in MAC.
CONCLUSIONS: The worse outcomes of rectal MAC appear to be driven largely by late-stage presentation, possibly owing to later diagnosis. MAC nonetheless carries a distinct immune phenotype, detectable even in histologically normal surrounding mucosa, that likely contributes to its treatment resistance. These observations provide a basis for developing histotype-specific approaches to both early detection and treatment in this uncommon but clinically challenging tumour subtype.