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IMMUNOREACT 17: CD8+ T LYMPHOCYTE EXHAUSTION IN ELDERLY PATIENTS WITH RECTAL CANCER
Laura Marinelli^*3, Andromachi Kotsafti⁴, Astghik Stepanyan¹, Gaia Tussardi¹, Melania Scarpa⁴, Antonio Rosato⁴, Ottavia De Simoni⁴, Francesca Bergamo⁴, Valerio Pellegrini⁵, Matteo Fassan⁵, Ivana Cataldo⁵, Carlotta Ceccon⁵, Anna Pozza⁵, Roberta Salmaso², Federico Scognamiglio¹, Cesare Ruffolo¹, Imerio Angriman², Silvia Negro², Chiara Vignotto¹, Luca Facci¹, Giorgio Rivella¹, Quoc R. Bao¹, Andrea Baldo¹, Giulia Pozza¹, Maurizio Zizzo⁶, Giovanni Pirozzolo⁷, Giovanni Bordignon⁷, Isabella Mondi⁷, Silvio Guerriero⁸, Giuseppe Portale⁹, Lavinia Ceccarini⁹, Mattia Barbareschi^3,10, Giovanni Bertalot^3,10, Alberto Brolese³, Giulia Noaro¹¹, Giulia Becherucci¹², Andrea Porzionato², Francesco Cavallin¹³, Barbara Di Camillo², Ignazio Castagliuolo², Gaya Spolverato², Marco Scarpa^2
1Chirurgia Generale 3, Azienda Ospedale Universita Padova, Padova, Veneto, Italy; ²Universita degli Studi di Padova, Padova, Veneto, Italy; ³Ospedale Santa Chiara di Trento, Trento, Trentino-Alto Adige, Italy; ⁴Istituto Oncologico Veneto IRCCS, Padova, Veneto, Italy; ⁵Azienda ULSS n 2 Marca Trevigiana, Treviso, Veneto, Italy; ⁶Azienda Unita Sanitaria Locale - IRCCS Tecnologie Avanzate e Modelli Assistenziali in Oncologia di Reggio Emilia, Reggio Emilia, Emilia-Romagna, Italy; ⁷Azienda ULSS 3 Serenissima, Venezia, Veneto, Italy; ⁸Azienda Sanitaria Territoriale Fermo, Porto San Giorgio, Italy; ⁹Azienda ULSS 7 Pedemontana, Bassano del Grappa, Veneto, Italy; ¹⁰Universita degli Studi di Trento, Trento, Trentino-Alto Adige, Italy; ¹¹Azienda ULSS 6 Euganea, Padova, Veneto, Italy; ¹²Azienda ULSS n 1 Dolomiti, Belluno, Veneto, Italy; ¹³Independent Statistician, Solagna, Veneto, Italy

Background
Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. The term "elderly rectal cancer" is generally defined as those occurring in patients aged 75 years or older. The tumor and peri-tumor microenvironment (TME) can significantly influence prognosis. A high density of cytotoxic CD8+ T lymphocytes, but not general T lymphocytes or regulatory T lymphocytes, correlates with better overall survival. The present study was conducted to investigate and compare the immune microenvironment within the rectal mucosa of young and elderly patients diagnosed with rectal cancer.
Methods
This study is a sub-analysis of data from the IMMUNOREACT project (clinicaltrials.gov NCT04915326 and NCT04917263) obtained from the healthy mucosa surrounding rectal cancer. 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 flow cytometry to determine the proportion of epithelial cells expressing CD80, CD86, CD40, HLA ABC, or HLA DR and of activated CD8+ T cells, CD4+ Th1 cells, and T reg. NanoString gene expression assay with the panCancer Immune profile was performed. Nonparametric tests were used for comparison.
Results
From the IMMUNOREACT database, we specifically excluded individuals diagnosed with T4 and/or M1 stages of cancer. Following these exclusion criteria, 952 patients were successfully enrolled in the study. In therapy-naïve elderly patients, the CD8/CD4 ratio in peritumoral healthy rectal mucosa was decreased (p=0.038), while PDL-1+ cell rate and CD3+CTLA4+ MFI tended to increase at immunohistochemistry and flow cytometry (p=0.066 and p=0.106). Moreover, in the whole group, transcriptomic analysis showed a direct correlation between the patient’s age and PD-1 (rho=0.42, p=0.06), LAG-3 (rho=0.38, p=0.10) and TIGIT (rho=0.38, p=0.10). At transcriptomics analysis, the trend plot of cell type scores showed an increase in exhausted CD8 T cells in patients over 75 years old.
Conclusion
Our study showed that elderly rectal cancer patients have a lower CD8/CD4 ratio, along with a more frequent expression of PD-L1 and a tendency toward higher expression of CTLA-4. Moreover, T lymphocyte exhaustion markers PD-1, LAG3, and TIGIT strongly correlated with patients' age. These data suggest that the aging immune system may eventually succumb to the effects of lymphocyte exhaustion. This phenomenon is commonly associated with aging, where the immune system’s capacity to respond to new threats diminishes over time, possibly allowing for the eventual development of malignancies even in strong initial defenses.

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