IMMUNOREACT 5: FEMALE PATIENTS WITH RECTAL CANCER HAVE A HIGHER EXPRESSION OF PDL-1 AND A HIGHER INFILTRATION OF T-CELLS WITHIN THE RECTAL MUCOSA.
Gaya Spolverato2, Matteo Fassan2,1, Giulia Capelli2, Melania Scarpa1, Valentina Chiminazzo2, Andromachi Kotsafti1, Imerio Angriman2, Michela Campi2, Ottavia De Simoni1, Cesare Ruffolo2, Astghik Stepanyan2, Chiara Vignotto2, Francesco Marchegiani2, Luca Facci2, Francesca Bergamo1, Stefano Brignola2, Gianluca Businello2, Vincenza Guzzardo2, Luca Dal Santo2, Roberta Salmaso2, Marco Massani5, Anna Pozza5, Ivana Cataldo5, Tommaso Stecca5, Angelo Dei Tos2, Vittorina Zagonel1, Pierluigi Pilati1, Boris Franzato1, Giovanni Pirozzolo4, Alfonso Recordare4, Roberto Merenda4, Giovanni Bordignon4, Silvio Guerriero6, Chiara Romiti6, Giuseppe Portale7, Chiara Cipollari7, Maurizio Zizzo3, Andrea Porzionato2, Marco Agostini2, 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, Surgery, Reggio Emilia, 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
Background
Sex is an important biological determinant of the immune response to cancer. Estrogens have been found to promote the expression of programmed death-ligand 1 (PD-L1) protein that has been associated with poor clinical outcomes of colorectal cancer (CRC) patients. Studies evaluating gender differences in the tumoral microenvironment in CRC are limited. Moreover, no previous study focused on the constitutive immune surveillance mechanism of patients with rectal cancer. The aim of the present study (IMMUNOlogical microenvironment in Rectal Adenocarcinoma Treatment, IMMUNOREACT 5) was to assess the differences in the rectal mucosa immune microenvironment between male and female patients.
Methods
A systematic review was conducted up to May 31st, 2021 including studies focusing on gender differences among tumoral microenvironment in patients with histologically confirmed colorectal or rectal cancer. A meta-analysis was performed, and a methodological quality assessment of the included studies was carried out.
A sub-analysis of the two twin IMMUNOREACT trials (NCT04915326 and NCT04917263), was aimed to detect gender differences in terms of healthy mucosa immune microenvironment in patients with early rectal cancer and patients with locally advanced rectal cancer who underwent neoadjuvant therapy, respectively. Immunohistochemistry and fluorescence-activated cell sorting were conducted on formalin-fixed paraffin-embedded (FFPE) slides and on fresh tissue samples obtained from normal rectal mucosa proximal to cancer or to the site of previous cancer.
Results
Eight studies were eligible for the analysis, reporting on PD-1 and PDL-1 expression in the CRC microenvironment; no one had sex differences in the gene expression as a primary endpoint. In male patients, the probability of having PD-1 (OR=0,748, 95%CI=0,561 to 0,998) and PD-L1 (OR=0,83, 95%CI= 0,748 to 0,922) positive tumor was lower than in females.
Female patients with T1-T2 rectal cancer had a higher number of activated CD4+ Th1 cells compared to male patients (p = 0.05); moreover, the expression of PDL-1 tended to be lower in male patients compared to the female population (p= 0.08). At IHC and FACS analysis, female patients with LARC who received neoadjuvant therapy had a higher infiltration of CK+CD86+ cells and activated CD8+ cells compared to their male counterparts (p= 0.029 and p= 0.012, respectively).
Conclusions
PDL-1 expression seems to be higher in women, who also tend to have a higher expression of Tumor-Infiltrating Lymphocytes (TILs). This could be due to women's higher estrogen levels, which have been proved to enhance PDL-1 expression in other tumors. Sex could be influencing immune response to rectal cancer and could be considered in therapeutic strategies. Particularly, anti-PDL-1 therapies could be more effective in women.
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