IMMUNOREACT 8: IMMUNE MARKERS AS PREDICTORS OF LOCAL TUMOR SPREAD IN PATIENTS UNDERGOING TRANSANAL EXCISION FOR RECTAL CANCER
Giulia Becherucci*1, Cesare Ruffolo1, Melania Scarpa2, Astghik Stepanyan1, Isacco Maretto1, Ottavia De Simoni2, Roberta Salmaso1, Gaya Spolverato1, Silvia Negro1, Imerio Angriman1, Andromachi Kotsafti1, Chiara Vignotto1, Federico Scognamiglio1, Maurizio Zizzo3, Francesco Marchegiani1, Luca Facci1, Francesca Bergamo2, Stefano Brignola1, Gianluca Businello1, Vincenza Guzzardo1, Luca Dal Santo1, Carlotta Ceccon1, Marco Massani4, Anna Pozza4, Ivana Cataldo4, Tommaso Stecca4, Angelo Dei Tos1, Vittorina Zagonel2, Pierluigi Pilati2, Boris Franzato2, Antonio Scapinello2, Beatrice Salmaso5, Giovanni Pirozzolo6, Andrea Porzionato2, Marco Agostini2, Quoc Riccardo Bao1, Francesco Cavallin1, Barbara Di Camillo1, Romeo Bardini1, Ignazio Castagliuolo1, Salvatore Pucciarelli1, Matteo Fassan1, Marco Scarpa1
1Chirurgia Generale 3, Azienda Ospedale Universita Padova, Padova, Veneto, Italy; 2Istituto Oncologico Veneto Istituto di Ricovero e Cura a Carattere Scientifico, Padova, Veneto, Italy; 3Arcispedale Santa Maria Nuova di Reggio Emilia, Reggio Emilia, Emilia-Romagna, Italy; 4Azienda ULSS n 2 Marca Trevigiana, Treviso, Veneto, Italy; 5Azienda ULSS 5 Polesana, Rovigo, Veneto, Italy; 6Azienda ULSS 3 Serenissima, Venezia, Veneto, Italy
Introduction: Trans anal excision (TAE) of rectal cancer can be considered as definitive treatment if the infiltration depth is T1 or lower, and the lesion is completely included within the resection margin. Moreover, it can be used as an alternative approach in case of a complete response to neoadjuvant therapy. The immune microenvironment within the bowel mucosa plays a role in the immune surveillance mechanisms against carcinogenesis. Our aim was to analyze the immune microenvironment in healthy rectal mucosa as possible predictor of tumor infiltration depth, lateral tumor spread, and complete response to neoadjuvant therapy of rectal cancer undergoing TAE.
Methods: This study is a sub-analysis of data from the IMMUNOREACT 1 and 2 trials (NCT04915326 and NCT04917263) including all the patients who underwent TAE of rectal cancer. In this multicentric study, we collected healthy mucosa surrounding the rectal cancer. A panel of immune markers was retrospectively investigated at immunohistochemistry: CD3, CD4, CD8, CD8beta, Tbet, FoxP3, PD-L1, MSH6, and PMS2 and CD80. A prospective analysis was performed with flow cytometry to determine the proportion of epithelial cells expressing CD80, CD86, CD40, HLA ABC or HLA DR and the proportion of activated CD8+ T cells, CD4+ Th1 cell, and T reg.
Results: A total of 64 patients with rectal cancer who were treated with TAE were analyzed: 41 in the retrospective cohort and 23 in the prospective cohort. In our study group, tumor infiltration depth over T1 stage was observed in 10 patients, lateral tumor spread in 8 patients, and complete response to neoadjuvant therapy in 19 ones. Deep tumor spread (over pT1 stage) was associated with a high CD8+/FoxP3+ T cells ratio (p=0.07), low CK+CD80+ mean fluorescence intensity (MFI) (p=0.032), high CK+CD86+ cell rate (p=0.008) and high CK+HLA-I + cell rate (p=0.038). Accuracy for predicting tumor infiltration depth was AUC=0.9 for CD8+/FoxP3+ T cells ratio, AUC=0.89 for CK+CD80+ MFI, AUC=0.98 for CK+CD86+ cell rate and AUC=0.98 for CK+HLA-I + cell rate. Accuracy for predicting lateral tumor spread was AUC=0.82 for CD8+CD38+ T cell rate, AUC=0.82 for CK+CD80+ MFI, and AUC=0.96 for CK+HLA-I + cell rate. Accuracy for predicting complete response was AUC=0.90 for CK+CD86+ cell rate, and AUC=0.8, p=0.017 for CK+HLA-I + cell rate.
Conclusion: In our series, patients with locally spreading rectal cancer that should undergo further surgery to complete rectal cancer treatment show higher antigen presentation within the healthy rectal mucosa surrounding the cancer. However, lymphocyte activation and co-stimulation are lower suggesting weak immune surveillance mechanisms. Similarly, In case of lack of complete response to neoadjuvant therapy, there is a higher antigen presentation by epithelial cells but low cytotoxic T cell activation.
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