RECTAL ADENOCARCINOMA: INFLUENCE OF BMI IN THE IMMUNOLOGICAL MICROENVIRONMENT OF PERITUMORAL HEALTHY MUCOSA - AN OBSERVATIONAL STUDY

Introduction: 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 mucosa. Patients and Methods: This study is a sub-analysis of data from the IMMUNOREACT 1 and 2 trials (NCT04915326 and NCT04917263). This multicentric study collected healthy mucosa surrounding the neoplasms of patients with early 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 or not, and between complete response or not, respectively. Results: A total of 213 patients with rectal cancer, whose data of 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 (BMI <25) while 125 were overweight or obese (BMI≥25). Obese/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 549 (377, 792) vs 416 (261, 663), 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 (CD8beta+ T cell /field: 87 (IQR: 60-106) 16 (IQR: 5-68), p=0.04). Finally, the infiltration of CD8+ T-cells in the healthy mucosa inversely correlated with BMI (rho=-0.34, p=0.03). Conclusions: Our findings suggest that in patients with rectal cancer, those who are obese/overweight have a lower activation of epithelial cells as antigen-presenting cells (APC cells) and a lower activation of cytotoxic T-cells (CD8+ 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.

Presupposti dello studio: Il cancro del retto rappresenta ~ il 35% della totale incidenza del cancro colorettale (CCR), terzo tumore più frequentemente diagnosticato a livello globale. Sebbene l'eziologia del carcinoma rettale sporadico non sia ancora completamente chiara, è stato dimostrato che diversi fattori di rischio aumentano la probabilità di sviluppare tale patologia, tra i quali dieta e obesità giocano un ruolo fondamentale: l'associazione tra BMI e incidenza del cancro del retto è stata ampiamente studiata ed è stato dimostrato che essa aumenta all’aumentare del BMI. L'importanza del microambiente tumorale e peritumorale nella promozione, crescita e progressione del cancro è ben riconosciuta: il microambiente immunitario è noto, infatti, per poter essere influenzato in diversi modi, arrivando a sopprimere la risposta immunitaria contro le cellule tumorali (favorendo l’“immunoevasione” delle stesse) o a controllarla positivamente (“immunosorveglianza”). In proposito, i linfociti infiltranti il tumore (TILs) hanno un ruolo cruciale nella sorveglianza immunitaria. L'obesità si associa a squilibrio adipochinico, disbiosi intestinale ed endotossiemia, nonché all’iperattivazione delle vie di signalling dell'IGF-1 e all’eccessivo rilascio di acidi grassi liberi (FFA) che possono influenzare il microambiente immunitario. Il cross-talk tra cellule tumorali e microambiente immunitario può essere rilevato nella normale mucosa "sana" che circonda il cancro, secondo il concetto di "campo di cancerizzazione". Sebbene studi precedenti descrivano l'impatto del sovrappeso e dell'obesità come fattori di rischio per lo sviluppo del cancro del retto, sono poche le informazioni relative alla possibile influenza di un elevato BMI sul microambiente immunitario della mucosa sana peritumorale.