T cell-mediated rejection and cancer risk in 579,905 organ transplant recipients.

10552 Background: Prolonged immunosuppression following organ transplant raises post-transplant malignancy (PTM) risk without affecting chronic rejection graft failure (CRGF) rates. Our study investigated if T cell responses during rejection could protect against cancer, whereas T cell suppression in PTM might prevent rejection. Methods: Data from 1987 to 2023 on adult first-time single-organ transplant recipients were collected from the UNOS-OPTN database, excluding those with a history of malignancy. Time-dependent Cox regression and landmark analyses (at 1, 2, 3, 5, 10, 15, and 20 years) were used to explore the link between rejection-induced graft failure (RGF) and PTM. Results: The study included 579,905 recipients (kidney 386,878, liver 108,390, heart 45,046, lung 37,643, pancreas 1,948), with a mean follow-up of 7.3 years. RGF occurred in 9.5% of recipients (kidney 12.1%, liver 1.8%, heart 3.9%, lung 12.0%, pancreas 10.2%; p<0.001), with 2.1% experiencing acute rejection graft failure (ARGF) and 7.4%, CRGF. PTM occurred in 12.0% of recipients (kidney 9.9%, liver 12.4%. heart 20.9%, lung 22.6%, pancreas 11.3%; p<0.001), including breast (0.5%), digestive (1.2%), genitourinary (1.7%), gynecologic (0.1%), head and neck (0.3%), hematologic (1.4%), musculoskeletal (0.1%), neurologic (0.0%), respiratory (1.1%), and skin/Kaposi sarcoma (6.4%). In recipients with RGF, PTM risk significantly decreased (HR 0.21 0.19-0.24; p<0.001), with consistent trends observed across seven time landmarks (HR 0.20-0.07; p<0.001). Both ARGF and CRGF were associated with lower PTM risk (HR 0.23 0.18-0.29, 0.21 0.19-0.24; p<0.001). In organ-specific analyses, kidney transplants showed similar outcomes for RGF, ARGF, and CRGF (HR 0.21-0.22; p<0.001). Lung transplants exhibited significant risk reductions with RGF (HR 0.44 0.22-0.89; p=0.02) and CRGF (HR 0.47 0.24-0.94; p=0.03), with no significant results in other organs. All findings remained consistent even after excluding re-transplantations and deaths due to rejection. Excluding PTM-related deaths from PTM cases significantly lowered RGF risk (HR 0.69 0.65-0.73; p<0.001), a trend that was consistent across all time landmarks (HR 0.51-0.80; p<0.001). This inverse pattern was seen in kidney, liver, heart, and lung transplants (HR 0.90 0.84-0.95, 0.21 0.11-0.38, 0.21 0.14-0.31, 0.18 0.14-0.23; p<0.001) but not in pancreas transplants (HR 1.62 0.69-3.77; p=0.27). Conclusions: This study shows that rejection lowers cancer risk in kidney and lung transplants and that PTM reduces rejection risk in kidney, liver, heart, and lung transplants. Implementing enhanced cancer screening for those who have not experienced rejection may be considered. Further research is needed to elucidate the underlying T cell biology specific to each type of transplant.