IMMUNOREACT 10: INFLUENCE OF BMI IN THE IMMUNOLOGICAL MICROENVIRONMENT OF PERITUMORAL HEALTHY MUCOSA IN RECTAL ADENOCARCINOMA
Chiara Vignotto1, Melania Scarpa2, Astghik Stepanyan1, Roberta Salmaso1, Andromachi Kotsafti2, Ottavia De Simoni2, Giulia Becherucci1, Silvia Negro1, Gaya Spolverato1, Federico Scognamiglio1, Nicole Maddalena Maturi1, Cesare Ruffolo1, Imerio Angriman1, Valentina Chiminazzo1, Isacco Maretto1, Maurizio Zizzo3, Francesca Bergamo2, Stefano Brignola4, Gianluca Businello5, 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 Salmaso*5, Giovanni Pirozzolo6, Alfonso Recordare6, Licia Laurino6, Andrea Porzionato2, Marco Agostini2, Quoc Riccardo Bao1, Francesco Cavallin7, Barbara Di Camillo8, Romeo Bardini1, Ignazio Castagliuolo1, Salvatore Pucciarelli1, Matteo Fassan1,2, 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 IRCCS, Surgery, Reggio Emilia, Reggio Emilia, Emilia Romagna, Italy; 4Azienda ULSS n 2 Marca Trevigiana, Treviso, Veneto, Italy; 5Azienda ULSS n 5 Polesana, Rovigo, Veneto, Italy; 6Azienda ULSS 3 Serenissima, Venezia, Veneto, Italy; 7Indipendent Statician, Solagna, Veneto, Italy; 8Universita degli Studi di Padova Dipartimento di Ingegneria Industriale, Padova, Veneto, Italy
The peritumoral microenvironment is known to act to suppress the immune response against cancer cells, and tumor-infiltrating lymphocytes have a crucial role in immune surveillance. Obesity leads to an imbalance in adipokines, gut dysbiosis, and endotoxemia, as well as IGF-1 activation pathways and free fatty acids release that can influence the immune microenvironment. The cross-talk between tumor cells and the immune microenvironment can be detected in the normal "healthy" mucosa surrounding cancer, according to the concept of the field of cancerization. The aim of this study is to analyze the healthy rectal mucosa surrounding rectal cancer in overweight/obese patients who underwent surgery to evaluate the potential alteration of immune surveillance mechanisms of healthy rectal mucosal
This study is a sub-analysis of data from the IMMUNOREACT 1 and 2 trials (NCT04915326 and NCT04917263). In this multicentric study, we collected healthy mucosa surrounding 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 fluorescence-activated cell sorting 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. Immune markers of healthy rectal mucosa were compared between patients under and over the BMI 25, between infiltrated margins, and between complete response or not, respectively.
A total of 213 patients with rectal cancer, whose data on body mass index were available, were analyzed: 103 in the retrospective cohort and 110 in the prospective cohort. In our study group, 88 patients were normal -weight while 125 were overweight or obese (BMI>25). Overweight patients with rectal cancer had a lower expression of HLA-ABC on the surface of their epithelial cells than those with BMI under 25 (CK+HLA-abc+ MFI (p= 0.069). In particular, in patients undergoing neoadjuvant therapy, overweight ones had a lower frequency of high expression of HLA-ABC on epithelial cells than normal-weight patients. Moreover, overweight patients had a lower infiltration of CD8beta+ T cells within the healthy mucosa surrounding the cancers than those with BMI under 25 (p=0.04). Finally, the infiltration of CD8+ T-cells in the healthy mucosa inversely correlated with BMI (rho=-0.34, p=0.03).
Our findings suggest that in patients with rectal cancer, those who are overweight have a lower activation of epithelial cells as antigen-presenting cells and a lower activation of cytotoxic T-cells in their healthy mucosa surrounding rectal cancer. These data could be useful to plan a tailored approach to overweight/obese patients with a rectal cancer diagnosis.
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