Thymopoiesis as a biomarker of cancer risk and outcome

Abstract T cells prevent cancer development and control its spread. Recent data showed that the thymus produces T cells late into adult life and is essential for health. We demonstrated that adults who underwent thymectomy have increased risk of mortality, cancer, and autoimmunity that correlates with decreased T cell production and a pro-inflammatory cytokine environment (PMID:37530823). Thymectomized adults primarily die of cancer (PMID:40472288). Others showed a widespread genetic variant in the T cell receptor gene, rs2204985, correlates with high (GG variant) vs low (AA variant) thymopoiesis with age. We hypothesized that the rs2204985 genotype would associate with resilience (GG) or vulnerability (AA) to cancer development and adverse cancer outcome. We further hypothesized that the functional marker of thymopoiesis, the abundance of signal joint T cell receptor excision circles (sjTREC) in blood, would associate with distinct outcomes from chronic hematologic malignancy. We gathered clinical data from 32,018 Mass General Brigham BioBank (MGBBB) patients. We calculated the incidence of new cancers from 2010-2020 amongst demographically similar patients with different rs2204985 genotypes. We conducted manual chart review to contrast clinical outcomes via Kaplan-Meier (KM) analysis in GG and AA patients with chronic lymphocytic leukemia (CLL), melanoma, and gastroesophageal (GEJ) cancers over 25 years post diagnosis. We performed sjTREC analysis on peripheral blood of 504 healthy MGBBB patients. Separating males and females, we established high vs low thresholds for sjTREC by comparing GG vs AA patients. We stratified 314 MGBBB CLL patients by high vs low thymopoiesis (N= 164 and 150) to correlate with clinical outcomes over 40 years post diagnosis via manual chart review. Compared to 15,172 GG patients, 16,846 AA patients had a higher 10-year risk of developing all cancers (HR[95% CI]: 1.06[1.03-1.09], p<0.001). AA patients had a higher 10-year risk of developing melanoma (1.1[1.06-1.20], p<0.001) and genitourinary cancers (1.2[1.02-1.32], p=0.02). These effects were preserved after excluding patients that had a prior history of cancer from the analysis. Given the prevalence of melanoma and GEJ cancers in the MGBBB and the known role of T cell control in preventing their progression from precursor states, we selected them for further study in rs2204985 genotyped patients. In 244 melanoma patients, the GG and AA groups (N=106 and 138) had similar morphologic classifications, pathologic characteristics, distributions of TNM staging, and demographics at diagnosis. In KM analysis over 25 years post diagnosis, progression free survival (PFS) was lower in AA patients (1.8[1.2-2.9], p=0.009) and risk of early-stage progression to metastatic disease was higher (RR 2.2[1.1-4.1], p=0.013). In AA patients with metastatic melanoma, metastases and relapses were more numerous (p<0.001; p=0.004). In KM analysis of 179 patients with GEJ cancer over 25 years post diagnosis, 89 AA patients had lower overall survival (OS) (HR 1.5[1.01-2.3], p=0.041) and PFS (1.7[1.1-2.6], p=0.016) with more numerous metastases (p=0.002) and relapses (p<0.001) than 90 GG patients. In melanoma and GEJ cancers, AA genotype associated with increased immune-related adverse events with immunotherapy (p<0.001; p=0.007). To investigate thymic control of chronic hematologic malignancy, we stratified CLL patients by high vs low thymopoiesis (N= 164 and N=150) via sjTREC. The groups had similar staging, cytogenetic and mutational profiles, demographics, hemoglobin A1c, glomerular filtration rate, and smoking history at diagnosis. In KM analysis over 40 years post diagnosis, low thymopoiesis associated with inferior OS (3.3[1.9-5.7], p<0.001). In KM analysis over 25 years post diagnosis, low thymopoiesis associated with inferior PFS (3.3[1.9-5.8], p<0.001) and higher incidence of relapse (p=0.042) and Richter's transformation to lymphoma (2.5[1.2-5.1], p=0.011). Despite similar selection of treatment regimens across groups, low thymopoiesis patients developed more cytogenetic abnormalities throughout their course of disease (p=0.012). These effects were also preserved in CLL patients stratified by rs2204985 genotype. Robust thymopoiesis independently associated with reduced cancer development and superior cancer outcomes in adults with CLL, melanoma, and GEJ cancers. Parameters of thymus function may be useful indicators of risk for some cancer types.