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IMMUNOREACT 12: PER-AND POLY-FLUOROALKYL SUBSTANCES (PFAS9 EXPOSURE IS ASSOCIATED WITH A LESS EFFICIENT ANTIGEN PRESENTATION IN HEALTHY MUCOSA OF RECTAL CANCER PATIENTS.
Luca Facci^*1, Giovanni Pirozzolo³, Melania Scarpa⁴, Sara Rosafio⁴, Astghik Stepanyan¹, Gaia Tussardi¹, Andromachi Kotsafti⁴, Antonio Rosato⁴, Ottavia De Simoni⁴, Francesca Bergamo⁴, Valerio Pellegrini⁵, Ivana Cataldo⁵, Carlotta Ceccon², Anna Pozza⁵, Roberta Salmaso², Cesare Ruffolo¹, Imerio Angriman², Gaya Spolverato², Silvia Negro¹, Chiara Vignotto¹, Giorgio Rivella¹, Quoc R. Bao¹, Andrea Baldo¹, Giulia Pozza¹, Maurizio Zizzo⁶, Giovanni Bordignon³, Roberto Merenda³, Isabella Mondi³, Daunia Verdi³, Silvio Guerriero⁷, Giuseppe Portale⁸, Lavinia Ceccarini⁸, Laura Marinelli⁹, Mattia Barbareschi^10,11, Giovanni Bertalot^10,11, Alberto Brolese⁹, Giulia Noaro¹², Giulia Becherucci¹³, Francesco Cavallin¹⁴, Barbara Di Camillo², Ignazio Castagliuolo², Matteo Fassan⁵, Marco Scarpa^2
1Chirurgia Generale 3, Azienda Ospedale Universita Padova, Padova, Veneto, Italy; ²Universita degli Studi di Padova, Padova, Veneto, Italy; ³Azienda ULSS 3 Serenissima, Venezia, Veneto, Italy; ⁴Istituto Oncologico Veneto IRCCS, Padova, Veneto, Italy; ⁵Azienda ULSS n 2 Marca Trevigiana, Treviso, Veneto, Italy; ⁶Arcispedale Santa Maria Nuova IRCCS, Reggio Emilia, Italy; ⁷Azienda Sanitaria Territoriale Fermo, Porto San Giorgio, Italy; ⁸Azienda ULSS 7 Pedemontana, Bassano del Grappa, Veneto, Italy; ⁹Ospedale Santa Chiara di Trento, Trento, Trentino-Alto Adige, Italy; ¹⁰Ospedale Santa Chiara di Trento Unita Operativa Anatomia Patologica, Trento, Trentino-Alto Adige, Italy; ¹¹Universita degli Studi di Trento, Trento, Trentino-Alto Adige, Italy; ¹²Azienda ULSS 6 Euganea, Padova, Veneto, Italy; ¹³Azienda ULSS n 1 Dolomiti, Belluno, Veneto, Italy; ¹⁴Independent Statistcian, Solagna, Italy

Background
Per- and poly-fluoroalkyl substances (PFAS) are synthetic chemicals classified as emerging contaminants that pose health risks to humans. Epidemiological studies have shown an association between PFAS exposure and immune function alterations, which may affect an effective antitumor response. This study aims to evaluate the potential effect of PFAS exposure on constitutive immunosurveillance mechanisms in the healthy rectal mucosa of patients with rectal cancer within the cohort of the IMMUNOREACT Project, which includes patients residing in a documented PFAS-contaminated community in North-Eastern Italy.

Methods
This study is a preliminary sub-analysis of data from the prospective arm of the IMMUNOREACT 1 project (clinicaltrials.gov NCT04915326) comparing patients from areas with high vs. low PFAS exposure. Rectal mucosa samples were retrospectively analyzed by immunohistochemical staining with a panel of immune markers (CD3, CD4, CD8, CD8beta, Tbet, FoxP3, PD-L1, MSH6, and PMS2 and CD80). A prospective analysis was performed with flow cytometry to determine the proportion of epithelial cells expressing CD80, CD86, HLA ABC, activated CD8+ T cells, CD4+ Th1 cells, and T reg. Non-parametric tests were used for comparison.

Results
In this series, we observed that, in the tumor tissue, the rate of epithelial antigen-presenting cells expressing CD80+, CD86+, and HLAabc+ is lower in the subjects coming from the high-risk zones, suggesting that the immunosurveillance could be somehow less active and with potential impairment of the presentation of the antigen. Similarly, in the healthy mucosa adjacent to the tumor, patients in the high-risk zones had fewer CD80+ epithelial antigen-presenting cells but a greater number of CD80+ immune cells. No differences were observed in terms of infiltrating lymphocytes.

Conclusion
According to our data, PFAS exposure seems to be associated with a lower ability of epithelial cells to present antigens either in cancer or in peritumoral tissue, while there is a higher antigen presentation by dendritic cells and macrophages. These data suggest that PFAS may impair the primary antigen presentation altering the epithelial cells-T lymphocyte cross-talk. This fascinating hypothesis should be verified in an in vitro model.

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