IMMUNOREACT 6: YOUNG PATIENTS WITH RECTAL CANCER HAVE A LOWER INFILTRATION OF CD4+ T CELLS WITHIN THE HEALTY RECTAL MUCOSA BUT NO MISMATCH REPAIR GENES DEFECTS.
Gaya Spolverato2, Matteo Fassan2,1, Melania Scarpa1, Valentina Chiminazzo2, Astghik Stepanyan2, Imerio Angriman2, Ottavia De Simoni1, Cesare Ruffolo2, Chiara Vignotto2, Isacco Maretto2, Francesca Bergamo1, Stefano Brignola2, Gianluca Businello2, Vincenza Guzzardo2, Roberta Salmaso2, Luca Dal Santo2, Francesco Marchegiani2, Marco Massani5, Anna Pozza5, Ivana Cataldo5, Tommaso Stecca5, Angelo Dei Tos2, Vittorina Zagonel1, Pierluigi Pilati1, Boris Franzato1, Giovanni Pirozzolo4, Alfonso Recordare4, Maurizio Zizzo3, Giovanni Bordignon4, Roberto Merenda4, Luca Facci2, Silvio Guerriero6, Chiara Romiti6, Giuseppe Portale7, Chiara Cipollari7, Giorgio Rivella2, Marco Agostini2, Andrea Porzionato2, Andromachi Kotsafti1, Francesco Cavallin8, Barbara Di Camillo9, Romeo Bardini2, Ignazio Castagliuolo2, Salvatore Pucciarelli2, Marco Scarpa*2
1Oncological Surgery Unit, Veneto Institute of Oncology (IOV-IRCCS), Padova, Italy; 2Azienda Ospedale Universita Padova, Padova, Veneto, Italy; 3Arcispedale Santa Maria Nuova IRCCS, Reggio Emilia, Italy; 4Azienda ULSS 3 Serenissima, Venezia, Veneto, Italy; 5Azienda ULSS n 2 Marca Trevigiana, Treviso, Veneto, Italy; 6ASUR 4, Ospedale di Fermo, Fermo, Italy; 7Azienda ULSS 6 Euganea, Padova, Veneto, Italy; 8Independent Statistician, Solagna, Italy; 9Universita degli Studi di Padova Dipartimento di Ingegneria Industriale, Padova, Veneto, Italy
Introduction:
The immune microenvironment within the bowel mucosa plays a role in the immune surveillance mechanisms against carcinogenesis. Colon cancer in young patients is often associated with Lynch syndrome or to familial polyposis but, in young patients with sporadic rectal cancer, mutations of DNA mismatch repair (MMR) or APC genes are rarely observed. The aim of this study was to analyze the features of the immune microenvironment in healthy rectal mucosa in young patients with rectal cancer.
Aims & Methods:
This study is a sub-analysis of data from the IMMUNOREACT 1 trial (NCT04915326). In this multicentric study, healthy mucosa surrounding the neoplasms of patients with early rectal cancer was collected. 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 50 years old, respectively. TGCA PanCancer Atlas rectal cancer series was used as a validation cohort.
Results:
A total of 441 patients with early rectal cancer were analyzed in the retrospective cohort: 35 (9%) of them were under 50 years old. None of the patients showed defects in mismatch repair genes expression. Patients under 50 years old had a lower rate of CD4+ T-cell infiltration within the healthy rectal mucosa and their CD4/CD3 ratio was significantly lower (p=0.007 and p=0.005, respectively). In the prospective cohort (6 patients <50 years and 35 ?50), younger patients showed a lower infiltration of CD8+CD28+ in the rectal mucosa and they tended to have a higher rate of CD3+CTLA-4+ T cells infiltration (p=0.05 and p=0.09, respectively).
The TGCA rectal cancer cohort included 155 patients (23 ones <50 vs 132 ones ?50). CD3 and CD69 mRNA expression were lower while CTLA-4 mRNA levels were higher in younger patients (p=0.08, p=0.03, and p=0.08, respectively). Mutation of PYHIN1, a mediator of the tumor suppressor activity of IFN, CD5L, a regulator of inflammatory responses and ASXL2, a member of a family of epigenetic regulators were more frequent in young patients (p<0.001, p<0.001, and p<0.001 respectively).
Conclusion:
In our series, young patients with rectal cancer showed a constitutive immune microenvironment within the rectal mucosa permissive for cancer progression with a low level of CD4+ T cell infiltration and a high CD3+CTLA4+ T cells infiltration. TCGA data confirmed these observations. Unexpectedly, no role seems to be played by mismatch repair genes defects but mutations of other regulators of inflammatory response seem to be involved.
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