Genetic control of lymphocyte infiltration in tumors in mice
Kakarlapudi, Neelima Raju
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A higher density of infiltrating T lymphocytes in cancers of several organs has been associated with a better prognosis. Numerous studies have elucidated the molecular pathways that govern the migration of T lymphocytes into tumor tissue. However it has not been clear WHY? some patients have denser infiltration than others. This thesis establishes that the host’s genes determine the density of infiltrating T lymphocytes in tumors. We mapped 9 Lynf (susceptibility to lymphocyte infiltration) loci which control the density of lymphocyte infiltration in ENU ( N -ethyl, N -nitrosourea) induced autochthonous lung tumors in mice. We confirmed the Lynf3 and Lynf4 loci in one and three additional independent crosses, respectively. This demonstrates the reproducibility and robustness of genetic control of tumor infiltration. We found that a higher density of infiltration is associated with a smaller tumor size and a more advanced histopathological phenotype in mouse lung tumors. This inverse relationship was found in two crosses involving different strains. We also report a novel type of locus on mouse Chromosome 2, which controls the relationship between the density of lymphocyte infiltration and tumor size. We searched for genes implicated in the trafficking of the lymphocytes which colocalize to the Lynf regions and found none. This suggests that the phenomenon is controlled by previously unknown genes. We determined that one of Lynf loci, the Lynf4 locus determines the proportion of CD4+ and CD8+ T lymphocytes in the spleens of 4 week old mice.