Loci controlling lymphocyte production of interferon gamma after alloantigen stimulation in vitro and their co-localization with genes controlling lymphocyte infiltration of tumors and tumor susceptibility

Low infiltration of lymphocytes into cancers is associated with poor prognosis, but the reasons why some patients exhibit a low and others a high infiltration of tumors are unknown. Previously we mapped four loci (Lynf1-Lynf4) controlling lymphocyte infiltration of mouse lung tumors. These loci do not encode any of the molecules that are involved in traffic of lymphocytes. Here we report a genetic relationship between these loci and the control of production of IFN gamma in allogeneic mixed lymphocyte cultures (MLC). We found that IFN gamma production by lymphocytes of O20/A mice is lower than by lymphocytes of OcB-9/Dem mice (both H2 (pz) ) stimulated in MLC by irradiated splenocytes of C57BL/10SnPh (H2 (b) ) or BALB/cHeA (H2 (d) ) mice, or by ConA. IFN gamma production in MLCs of individual (O20 x OcB-9)F(2) mice stimulated by irradiated C57BL/10 splenocytes and genotyped for microsatellite markers revealed four IFN gamma-controlling loci (Cypr4-Cypr7), each of which is closely linked with one of the four Lynf loci and with a cluster of susceptibility genes for different tumors. This suggests that inherited differences in certain lymphocyte responses may modify their propensity to infiltrate tumors and their capacity to affect tumor growth.