Genetic influence on lymphocyte repopulation in thymus
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In cancers of colon, ovary, lung, and melanomas, intensity of CD3 + lymphocyte infiltration is correlated with a better prognosis. Previous studies of tumor infiltration analyzed lymphocyte trafficking to the tumor and found that it requires expression of specialized molecules on circulating lymphocytes and on vascular endothelium, as well as production of cytokines and chemokines to direct lymphocyte migration to the tumor. However, a previous study from this laboratory mapped nine gene-loci, Lynf1-9, which impact degree of tumor infiltration and surprisingly, these genes are distinct from all genes involved in lymphocyte trafficking. Thus, trafficking factors are not determining individual propensity to tumor infiltration. Analysis of lymphocyte infiltration in lung tumors of two different mouse strains, O20/A and OcB-9, revealed differences in the degree of infiltration, with a higher infiltration being associated with smaller tumor size. Because the previous study observed that the degree of infiltration is regulated by the host's genes ( Lynf1-9 ), other biological effects of the Lynf loci were analyzed. Lynf4 showed a strong effect on tumor infiltration: mice with two Lynf4 BB alleles had much denser tumor infiltration than those with two Lynf4 OO alleles. We hypothesized that Lynf4 could be influencing immunological functions or immune organ composition. We show here significant differences in the frequency of double positive CD4 + CD8 + cells in the thymus of eight to ten week old F 2 mice with different Lynf4 alleles after treatment with a combination of irinotecan (CPT-11) and 5-fluorouracil (5-FU). We demonstrate the robustness of the genetic control of the lymphocyte repopulation of the thymus. Lynf genes may reflect the link between cellular composition of the thymus and possibly other lymphoid organs and the quantity of cells infiltrating a tumor. A better understanding of this phenotypic trait and how genes regulate CD4 + and CD8 + cells in the thymus could allow for a more personalized treatment approach and answer the question as to why differences exist in the degree of lymphocyte infiltration among individuals with tumors.