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IMMUNOREACT 18: FAMILIAL PREDISPOSITION TO COLORECTAL CANCER AFFECTS THE IMMUNE LANDSCAPE IN RECTAL CANCER PATIENTS.
Silvia Negro², Melania Scarpa^*3, Astghik Stepanyan¹, Sara Vedovato², Gaia Tussardi¹, Andromachi Kotsafti³, Antonio Rosato³, Ottavia De Simoni³, Francesca Bergamo³, Emanuele D. Urso², Valerio Pellegrini⁴, Ivana Cataldo⁴, Carlotta Ceccon², Anna Pozza⁴, Roberta Salmaso², Cesare Ruffolo¹, Imerio Angriman², Chiara Vignotto¹, Luca Facci¹, Giorgio Rivella¹, Andrea Baldo¹, Giulia Pozza¹, Maurizio Zizzo⁵, Giovanni Pirozzolo⁶, Giovanni Bordignon⁶, Roberto Merenda⁶, Licia Laurino⁶, Isabella Mondi⁶, Silvio Guerriero⁷, Giuseppe Portale⁸, Lavinia Ceccarini⁸, Laura Marinelli⁹, Mattia Barbareschi^9,10, Giovanni Bertalot^9,10, Alberto Brolese⁹, Giulia Noaro¹¹, Giulia Becherucci¹², Andrea Porzionato², Francesco Cavallin¹³, Barbara Di Camillo², Gaya Spolverato², Ignazio Castagliuolo², Matteo Fassan^4,2, Marco Scarpa^2
1Chirurgia Generale 3, Azienda Ospedale Universita Padova, Padova, Veneto, Italy; ²University of Padova, Padova, Not required for this country, Italy; ³Istituto Oncologico Veneto IRCCS, Padova, Veneto, Italy; ⁴Azienda ULSS 2 Marca Trevigiana, Treviso, Italy; ⁵Azienda Unita Sanitaria Locale - IRCCS Tecnologie Avanzate e Modelli Assistenziali in Oncologia di Reggio Emilia, Reggio Emilia, Italy; ⁶Azienda ULSS 3 Serenissima, Venezia, Italy; ⁷ASUR Area Vasta 4 Fermo, Fermo, Italy; ⁸Azienda ULSS 7 Pedemontana, Santorso, Italy; ⁹Ospedale Santa Chiara di Trento, Trento, Trentino-Alto Adige/South Tyrol, Italy; ¹⁰Universita degli Studi di Trento, Trento, Trentino-Alto Adige/South Tyrol, Italy; ¹¹Azienda ULSS 6 Euganea, Padua, Veneto, Italy; ¹²Azienda ULSS n 1 Dolomiti, Belluno, Veneto, Italy; ¹³Independent Statistician, Solagna, Veneto, Italy

Background: Studies evaluating differences in the rectal cancer tumor microenvironment in patients with a familial predisposition to colorectal cancer (CRC) are limited. Furthermore, no previous study has specifically focused on patients with a familial predisposition but no identifiable genetic mutations. This study aimed to evaluate the immune landscape of the rectal mucosa in these patients, defined as those with at least one first-degree relative with CRC but no known genetic mutations (FDR+).
Methods: This study is a sub-analysis of the dataset of the IMMUNOREACT project (clinicaltrials.gov NCT04915326 and NCT04917263) obtained from the healthy mucosa surrounding rectal cancer in patients prospectively enrolled between 2018 and 2024. Patients were stratified into two cohorts based on familial CRC history: FDR+ (familial predisposition) and FDR- (no familial predisposition). The immune microenvironment of healthy rectal mucosa was evaluated and compared between the FDR+ and FDR- groups using immunohistochemistry and flow cytometry. Key immune parameters, including T cell subsets and antigen presentation markers, were analyzed to identify potential immune changes associated with familial predisposition.
Results: A total of 104 patients were included in the study, of whom 25(24%) were classified as FDR+. All of them proficiently expressed MMR genes on immunohistochemistry in their healthy rectal mucosa and none of them had any polyposis (>10 polyps). FDR+ patients a higher tumor stage (p=0.02). The FDR+ group exhibited distinct immune characteristics in their healthy rectal mucosa. They had increased CD8+CD38+ and CD8+CD28+ T cell rates (p=0.06 and p=0.01, respectively). Conversely, these patients demonstrated significantly reduced HLA-ABC expression in their epithelia cells (p=0.05).
Conclusions: The immune microenvironment in rectal cancer patients with a familial predisposition to CRC but no identified genetic mutations is characterized by a paradoxical combination of increased cytotoxic T-cell activation and impaired antigen presentation by epithelial cells. The increased cytotoxic activation might result from their interplay with macrophages and dendritic cells which might not be as effective as the primary one with epithelial cells. This distinctive immune profile may explain the association with more advanced tumor stages observed in these patients. Further studies are needed to explore the impairment of antigen presentation by epithelial cells which might be the key point of immune surveillance failure in these patients.

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