Distinct immunogenomic features of cancers arising in solid organ transplant recipients.

10587 Background: Solid organ transplantation recipients (SOTRs) are at increased risk of cancer due to long-term immunosuppressive therapy to prevent organ rejection. However, the immunogenomic characteristics of cancers arising in SOTRs remain poorly defined, limiting evidence-based treatment decisions, particularly regarding immunotherapy. Methods: Next-generation sequencing (NGS) of tumor tissue for DNA (592-gene panel/whole exome) and RNA (whole transcriptome) was carried out at Caris Life Sciences for SOTRs (n=1,024) and individuals without a transplant matched by age, sex, and cancer type (10:1 ratio, n=10,240). Immune cell infiltration in the tumor microenvironment (TME) was estimated by quanTIseq. Interferon-gamma (IFN-γ) signaling was assessed by a 10-gene transcriptomic signature. Tumor mutational burden (TMB) was assessed by NGS. Microsatellite instability (MSI) was assessed by immunohistochemistry (IHC) and NGS, and PD-L1 expression by IHC. Among SOTRs treated with immunotherapy, overall survival was assessed from insurance claims and calculated from treatment initiation to last contact. Results: The median age at sample collection was 65 years, with kidney recipients comprising the majority of SOTR cases (59.6%). Non-small cell lung cancer (NSCLC) was the most common malignancy (18.5%), followed by colorectal cancer (CRC, 10.5%). For all tumors combined, SOTRs exhibited significantly reduced adaptive immune cell infiltration in the TME, including CD8 + T-cells (SOTR vs non-SOTR median: 0.11% vs 0.23%), regulatory T-cells (1.60% vs 2.10%) and B-cells (3.69% vs 3.91%); no significant differences were observed in innate immune cell fractions except for myeloid dendritic cells (0.64% vs 0.79%). While IFN-γ signatures were similar among all SOTRs and non-SOTRs, SOTRs had significantly lower IFN-γ for NSCLC and cutaneous squamous cell carcinoma (cSCC). Median TMB was significantly higher in SOTRs than non-SOTRs for NSCLC, colorectal cancer (CRC), pancreatic cancer, cSCC, melanoma, and esophageal cancer. MSI was more common in SOTRs overall (4.9% vs 1.9%; p<0.0001) and for CRC (15.8% vs. 6.8%; p <0.0001). PD-L1 positivity was less common in SOTRs than non-SOTRs (12.4% vs 18.6%; p=0.021). Finally, among SOTRs treated with immunotherapy, those with high TMB (≥10 mutations/Mb) tended to have better survival than those with low TMB (hazard ratio 0.79, 95%CI 0.47-1.34, p=0.374). Conclusions: Despite higher prevalence of tumors with high TMB and MSI for select cancer types, SOTRs had lower adaptive immune infiltration and IFN-γ signaling within the TME, likely reflecting the immunosuppressive anti-rejection treatment. Our findings highlight distinct immunogenomic features of transplant-associated cancers and provide biologic rationale for further study of immunotherapy strategies in carefully selected SOTRs.