IMMUNOREACT 6: weak immune surveillance characterizes early-onset rectal cancer
Authors: Spolverato Gaya , Fassan Matteo , Scarpa Melania , Stepanyan Astghik , De Simoni Ottavia , Scognamiglio Federico , Chiminazzo Valentina , De Nardi Clarissa , Tamponi Giulia , Negro Silvia , Angriman Imerio , Kotsafti Andromachi , Ruffolo Cesare , Vignotto Chiara , Zizzo Maurizio , Marchegiani Francesco , Facci Luca , Bergamo Francesca , Brignola Stefano , Businello Gianluca , Guzzardo Vincenza , Dal Santo Luca , Salmaso Roberta , Ceccon Carlotta , Massani Marco , Pozza Anna , Cataldo Ivana , Stecca Tommaso , Dei Tos Angelo Paolo , Zagonel Vittorina , Pilati Pierluigi , Franzato Boris , Scapinello Antonio , Pirozzolo Giovanni , Recordare Alfonso , Merenda Roberto , Bordignon Giovanni , Laurino Licia , Guerriero Silvio , Romiti Chiara , Portale Giuseppe , Cipollari Chiara , Candioli Salvatore , Gavagna Laura , Pozza Giulia , Godina Mario , Mondi Isabella , Noaro Giulia , Ortenzi Monica , Guerrieri Mario , Tagliente Giovanni , Tomassi Monica , Tedeschi Umberto , Porzionato Andrea , Agostini Marco , Maretto Isacco , Bao Quoc Riccardo , Cavallin Francesco , Di Camillo Barbara , Bardini Romeo , Castagliuolo Ignazio , Pucciarelli Salvatore , Scarpa Marco ,   IMMUNOREACT Study Group, Capelli Giulia , Campi Michela , Saadeh Luca , Parini Dario , Prando Daniela , Salmaso Beatrice , Buzzi Gianluca , Di Cristofaro Loretta , Da Lio Corrado , Becherucci Giulia , Ricagna Fabio , Cola Roberto 
Published: July 2023

Abstract

Background
Colon cancer in young patients is often associated with hereditary syndromes; however, in early-onset rectal cancer, mutations of these genes are rarely observed. The aim of this study was to analyse the features of the local immune microenvironment and the mutational pattern in early-onset rectal cancer.

Methods
Commonly mutated genes were analysed within a rectal cancer series from the University Hospital of Padova. Mutation frequency and immune gene expression in a cohort from The Cancer Genome Atlas (‘TCGA’) were compared and immune-cell infiltration levels in the healthy rectal mucosa adjacent to rectal cancers were evaluated in the IMMUNOlogical microenvironment in REctal AdenoCarcinoma Treatment 1 and 2 (‘IMMUNOREACT’) series.

Results
In the authors’ series, the mutation frequency of BRAF, KRAS, and NRAS, as well as microsatellite instability frequency, were not different between early- and late-onset rectal cancer. In The Cancer Genome Atlas series, among the genes with the most considerable difference in mutation frequency between young and older patients, seven genes are involved in the immune response and CD69, CD3, and CD8β expression was lower in early-onset rectal cancer. In the IMMUNOlogical microenvironment in REctal AdenoCarcinoma Treatment 1 and 2 series, young patients had a lower rate of CD4+ T cells, but higher T regulator infiltration in the rectal mucosa.

Conclusion
Early-onset rectal cancer is rarely associated with common hereditary syndromes. The tumour microenvironment is characterized by a high frequency of mutations impairing the local immune surveillance mechanisms and low expression of immune editing-related genes. A constitutively low number of CD4 T cells associated with a high number of T regulators indicates an imbalance in the immune surveillance mechanisms.