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 IFNγ in allogeneic mixed lymphocyte cultures (MLC). We found that IFNγ production by lymphocytes of O20/A mice is lower than by lymphocytes of OcB-9/Dem mice (both H2pz) stimulated in MLC by irradiated splenocytes of C57BL/10SnPh (H2b) or BALB/ cHeA (H2d) mice, or by ConA. IFNγ production in MLCs of individual (O20 9 OcB-9)F2mice stimulated by irradiated C57BL/10 splenocytes and genotyped for microsatellite markers revealed four IFNγ-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.

Institute of Molecular Genetics Academy of Sciences of the Czech Republic Vídenká 1083 14220 Prague 4 Czech Republic

Zobrazit více v PubMed

de Visser KE, Eichten A, Coussens LM. Paradoxical roles of the immune system during cancer development. Nat Rev Cancer. 2006;6:24–37. doi: 10.1038/nrc1782. PubMed DOI

Klein G, Imreh S, Zabarovsky ER. Why do we not all die of cancer at an early age? Adv Cancer Res. 2007;98:1–16. doi: 10.1016/S0065-230X(06)98001-4. PubMed DOI

Smyth MJ, Dunn GP, Schreiber RD. Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv Immunol. 2006;90:1–50. doi: 10.1016/S0065-2776(06)90001-7. PubMed DOI

Willimsky G, Blankenstein T. The adaptive immune response to sporadic cancer. Immunol Rev. 2007;220:102–112. doi: 10.1111/j.1600-065X.2007.00578.x. PubMed DOI

Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoue F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pages F. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–1964. doi: 10.1126/science.1129139. PubMed DOI

Bui JD, Uppaluri R, Hsieh CS, Schreiber RD. Comparative analysis of regulatory and effector T cells in progressively growing versus rejecting tumors of similar origins. Cancer Res. 2006;66:7301–7309. doi: 10.1158/0008-5472.CAN-06-0556. PubMed DOI

Chen Q, Wang WC, Evans SS. Tumor microvasculature as a barrier to antitumor immunity. Cancer Immunol Immunother. 2003;52:670–679. doi: 10.1007/s00262-003-0425-4. PubMed DOI PMC

Horlings H, Demant P. Lung tumor location and lymphocyte infiltration in mice are genetically determined. Exp Lung Res. 2005;31:513–525. doi: 10.1080/01902140590918740. PubMed DOI

Kakarlapudi N, Vernooy JH, Quan L, Fijneman RJ, Demant P. Control of lymphocyte infiltration of lung tumors in mice by host’s genes: mapping of four Lynf (lymphocyte infiltration) loci. Cancer Immunol Immunother. 2008;57:217–225. doi: 10.1007/s00262-007-0367-3. PubMed DOI PMC

Fijneman RJ, Vos M, Berkhof J, Demant P, Kraal G. Genetic analysis of macrophage characteristics as a tool to identify tumor susceptibility genes: mapping of three macrophage-associated risk inflammatory factors, marif1, marif2, and marif3 . Cancer Res. 2004;64:3458–3464. doi: 10.1158/0008-5472.CAN-03-3767. PubMed DOI

Lipoldová M, Havelková H, Badalová J, Demant P. Novel loci controlling lymphocyte proliferative response to cytokines and their clustering with loci controlling autoimmune reactions, macrophage function and lung tumor susceptibility. Int J Cancer. 2005;114:394–399. doi: 10.1002/ijc.20731. PubMed DOI

Bodmer WF, Jones EA, Barnstable CJ, Bodmer JG. Genetics HLA: the major human histocompatibility system. Proc R Soc Lond B Biol Sci. 1978;202:93–116. doi: 10.1098/rspb.1978.0059. PubMed DOI

Huber BT. Mls genes and self-superantigens. Trends Genet. 1992;8:399–402. PubMed

Feng X, Hui KM, Younes HM, Brickner AG. Targeting minor histocompatibility antigens in graft versus tumor or graft versus leukemia responses. Trends Immunol. 2008;29:624–632. doi: 10.1016/j.it.2008.09.004. PubMed DOI PMC

Rychlikova M, Demant P, Ivanyi P. The mixed lymphocyte reaction in H-2K, H-2D, and non-H-2 incompatibility. Biomedicine. 1973;18:401–407. PubMed

Holán V, Havelková H, Krulová M, Demant P, Lipoldová M. A novel alloreactivity-controlling locus, Alan1, mapped to mouse chromosome 17. Immunogenetics. 2000;51:755–757. doi: 10.1007/s002510000197. PubMed DOI

Havelková H, Badalová J, Demant P, Lipoldová M. A new type of genetic regulation of allogeneic response. A novel locus on mouse chromosome 4, Alan2 controls MLC reactivity to three different alloantigens: C57BL/10, BALB/c and CBA. Genes Immun. 2000;1:483–487. doi: 10.1038/sj.gene.6363711. PubMed DOI

Demant P, Hart AA. Recombinant congenic strains—a new tool for analyzing genetic traits determined by more than one gene. Immunogenetics. 1986;24:416–422. doi: 10.1007/BF00377961. PubMed DOI

Holan V, Lipoldová M, Demant P. Identical genetic control of MLC reactivity to different MHC incompatibilities, independent of production of and response to IL-2. Immunogenetics. 1996;44:27–35. doi: 10.1007/BF02602654. PubMed DOI

Havelková H, Holan V, Karnik L, Lipoldová M. Mouse model for analysis of non-MHC genes that influence allogeneic response: recombinant congenic strains of OcB/Dem series that carry identical H2 locus. Central European Journal of Biology. 2006;1:16–28. doi: 10.2478/s11535-006-0002-x. DOI

Schoenborn JR, Wilson CB. Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol. 2007;96:41–101. doi: 10.1016/S0065-2776(07)96002-2. PubMed DOI

Street SE, Trapani JA, MacGregor D, Smyth MJ. Suppression of lymphoma and epithelial malignancies effected by interferon gamma. J Exp Med. 2002;196:129–134. doi: 10.1084/jem.20020063. PubMed DOI PMC

Enzler T, Gillessen S, Manis JP, Ferguson D, Fleming J, Alt FW, Mihm M, Dranoff G. Deficiencies of GM-CSF and interferon gamma link inflammation and cancer. J Exp Med. 2003;197:1213–1219. doi: 10.1084/jem.20021258. PubMed DOI PMC

Qin Z, Kim HJ, Hemme J, Blankenstein T. Inhibition of methylcholanthrene-induced carcinogenesis by an interferon gamma receptor-dependent foreign body reaction. J Exp Med. 2002;195:1479–1490. doi: 10.1084/jem.20011887. PubMed DOI PMC

Blankenstein T. The role of tumor stroma in the interaction between tumor and immune system. Curr Opin Immunol. 2005;17:180–186. doi: 10.1016/j.coi.2005.01.008. PubMed DOI

Klein J. Immunologically important loci. In: Lyon M, Searle A, editors. Genetic variants and strains of the laboratory mouse. Oxford: Oxford University Press; 1989.

Stassen AP, Groot PC, Eppig JT, Demant P. Genetic composition of the recombinant congenic strains. Mamm Genome. 1996;7:55–58. doi: 10.1007/s003359900013. PubMed DOI

Lipoldová M, Kosarová M, Zajicová A, Holán V, Hart AA, Krulová M, Demant P. Separation of multiple genes controlling the T-cell proliferative response to IL-2 and anti-CD3 using recombinant congenic strains. Immunogenetics. 1995;41:301–311. doi: 10.1007/BF00172155. PubMed DOI

Dietrich W, Katz H, Lincoln SE, Shin HS, Friedman J, Dracopoli NC, Lander ES. A genetic map of the mouse suitable for typing intraspecific crosses. Genetics. 1992;131:423–447. PubMed PMC

Tripodis N, Hart AA, Fijneman RJ, Demant P. Complexity of lung cancer modifiers: mapping of thirty genes and twenty-five interactions in half of the mouse genome. J Natl Cancer Inst. 2001;93:1484–1491. doi: 10.1093/jnci/93.19.1484. PubMed DOI

Lander E, Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet. 1995;11:241–247. doi: 10.1038/ng1195-241. PubMed DOI

Kosarová M, Havelková H, Krulová M, Demant P, Lipoldová M. The production of two Th2 cytokines, interleukin-4 and interleukin-10, is controlled independently by locus Cypr1 and by loci Cypr2 and Cypr3, respectively. Immunogenetics. 1999;49:134–141. doi: 10.1007/s002510050472. PubMed DOI

Groot PC, Moen CJ, Dietrich W, Stoye JP, Lander ES, Demant P. The recombinant congenic strains for analysis of multigenic traits: genetic composition. FASEB J. 1992;6:2826–2835. PubMed

Demant P. Cancer susceptibility in the mouse: genetics, biology and implications for human cancer. Nat Rev Genet. 2003;4:721–734. doi: 10.1038/nrg1157. PubMed DOI

Cui J, Shin T, Kawano T, Sato H, Kondo E, Toura I, Kaneko Y, Koseki H, Kanno M, Taniguchi M. Requirement for Valpha14 NKT cells in IL-12-mediated rejection of tumors. Science. 1997;278:1623–1626. doi: 10.1126/science.278.5343.1623. PubMed DOI

Blanchard DK, Djeu JY, Klein TW, Friedman H, Stewart WE., 2nd Interferon-gamma induction by lipopolysaccharide: dependence on interleukin 2 and macrophages. J Immunol. 1986;136:963–970. PubMed

Murata Y, Ohteki T, Koyasu S, Hamuro J. IFN-gamma and pro-inflammatory cytokine production by antigen-presenting cells is dictated by intracellular thiol redox status regulated by oxygen tension. Eur J Immunol. 2002;32:2866–2873. doi: 10.1002/1521-4141(2002010)32:10<2866::AID-IMMU2866>3.0.CO;2-V. PubMed DOI

Vilcek J, Henriksen-Destefano D, Siegel D, Klion A, Robb RJ, Le J. Regulation of IFN-gamma induction in human peripheral blood cells by exogenous and endogenously produced interleukin 2. J Immunol. 1985;135:1851–1856. PubMed

Sadler AJ, Williams BR. Interferon-inducible antiviral effectors. Nat Rev Immunol. 2008;8:559–568. doi: 10.1038/nri2314. PubMed DOI PMC

Kim KJ, Chaouat G, Leiserson WM, King J, De Maeyer E. Characterization of T-cell-soluble factors modulating the expression of Ia and H-2 antigens on BALB/c B lymphoma cell lines. Cell Immunol. 1983;76:253–267. doi: 10.1016/0008-8749(83)90368-4. PubMed DOI

Kaplan DH, Shankaran V, Dighe AS, Stockert E, Aguet M, Old LJ, Schreiber RD. Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci USA. 1998;95:7556–7561. doi: 10.1073/pnas.95.13.7556. PubMed DOI PMC

Nagase H, Mao JH, Balmain A. Allele-specific Hras mutations and genetic alterations at tumor susceptibility loci in skin carcinomas from interspecific hybrid mice. Cancer Res. 2003;63:4849–4853. PubMed

Festing MF, Lin L, Devereux TR, Gao F, Yang A, Anna CH, White CM, Malkinson AM, You M. At least four loci and gender are associated with susceptibility to the chemical induction of lung adenomas in A/J × BALB/c mice. Genomics. 1998;53:129–136. doi: 10.1006/geno.1998.5450. PubMed DOI

Wang H, Teske D, Tess A, Kohlhepp R, Choi Y, Kendziorski C, Moser AR. Identification of novel modifier loci of Apc Min affecting mammary tumor development. Cancer Res. 2007;67:11226–11233. doi: 10.1158/0008-5472.CAN-07-2487. PubMed DOI

Lee GH, Bugni JM, Obata M, Nishimori H, Ogawa K, Drinkwater NR. Genetic dissection of susceptibility to murine ovarian teratomas that originate from parthenogenetic oocytes. Cancer Res. 1997;57:590–593. PubMed

Tripodis N, Demant P. Genetic analysis of three-dimensional shape of mouse lung tumors reveals eight lung tumor shape-determining (Ltsd) loci that are associated with tumor heterogeneity and symmetry. Cancer Res. 2003;67:125–131. PubMed

Lee GH, Ogawa K, Nishimori H, Drinkwater NR. Most liver epithelial cell lines from C3B6F1 mice exhibit parentally-biased loss of heterozygosity at the Lci (Liver cell immortalization) locus on chromosome 4. Oncogene. 1995;11:2281–2287. PubMed

Cool M, Depault F, Jolicoeur P. Fine allelotyping of Erbb2-induced mammary tumors in mice reveals multiple discontinuous candidate regions of tumor-suppressor loci. Genes Chromosomes Cancer. 2006;45:191–202. doi: 10.1002/gcc.20276. PubMed DOI

Meruelo D, Offer M, Flieger N. Genetics of susceptibility for radiation-induced leukemia. Mapping of genes involved to chromosomes 1, 2, and 4, and implications for a viral etiology in the disease. J Exp Med. 1981;154:1201–1211. doi: 10.1084/jem.154.4.1201. PubMed DOI PMC

Santos J, Herranz M, Perez de Castro I, Pellicer A, Fernandez-Piqueras J. A new candidate site for a tumor suppressor gene involved in mouse thymic lymphomagenesis is located on the distal part of chromosome 4. Oncogene. 1998;17:925–929. doi: 10.1038/sj.onc.1202009. PubMed DOI

Zhu XX, Kozarsky K, Strahler JR, Eckerskorn C, Lottspeich F, Melhem R, Lowe J, Fox DA, Hanash SM, Atweh GF. Molecular cloning of a novel human leukemia-associated gene. Evidence of conservation in animal species. J Biol Chem. 1989;264:14556–14560. PubMed

Cool M, Jolicoeur P. Elevated frequency of loss of heterozygosity in mammary tumors arising in mouse mammary tumor virus/neu transgenic mice. Cancer Res. 1999;59:2438–2444. PubMed

Fijneman RJ, Jansen RC, van der Valk MA, Demant P. High frequency of interactions between lung cancer susceptibility genes in the mouse: mapping of Sluc5 to Sluc14 . Cancer Res. 1998;58:4794–4798. PubMed

Fijneman RJ, Demant P. A gene for susceptibility to small intestinal cancer, ssic1, maps to the distal part of mouse chromosome 4. Cancer Res. 1995;55:3179–3182. PubMed

Matsuda Y, Ozaki T, Enomoto H, Saito T, Sakiyama S. Chromosome mapping of the mouse and rat homologs of the human DAN gene, D1S1733E. Mamm Genome. 1996;7:709–710. doi: 10.1007/s003359900216. PubMed DOI

Mock BA, Krall MM, Dosik JK. Genetic mapping of tumor susceptibility genes involved in mouse plasmacytomagenesis. Proc Natl Acad Sci USA. 1993;90:9499–9503. doi: 10.1073/pnas.90.20.9499. PubMed DOI PMC

Dorward AM, Shultz KL, Horton LG, Li R, Churchill GA, Beamer WG. Distal Chr 4 harbors a genetic locus (Gct1) fundamental for spontaneous ovarian granulosa cell tumorigenesis in a mouse model. Cancer Res. 2005;65:1259–1264. doi: 10.1158/0008-5472.CAN-04-2992. PubMed DOI

Bliskovsky V, Ramsay ES, Scott J, DuBois W, Shi W, Zhang S, Qian X, Lowy DR, Mock BA. Frap, FKBP12 rapamycin-associated protein, is a candidate gene for the plasmacytoma resistance locus Pctr2 and can act as a tumor suppressor gene. Proc Natl Acad Sci USA. 2003;100:14982–14987. doi: 10.1073/pnas.2431627100. PubMed DOI PMC

van Wezel T, Ruivenkamp CA, Stassen AP, Moen CJ, Demant P. Four new colon cancer susceptibility loci, Scc6 to Scc9 in the mouse. Cancer Res. 1999;59:4216–4218. PubMed

Bernichtein S, Petretto E, Jamieson S, Goel A, Aitman TJ, Mangion JM, Huhtaniemi IT. Adrenal gland tumorigenesis after gonadectomy in mice is a complex genetic trait driven by epistatic loci. Endocrinology. 2008;149:651–661. doi: 10.1210/en.2007-0925. PubMed DOI PMC

Ko MS, Kitchen JR, Wang X, Threat TA, Wang X, Hasegawa A, Sun T, Grahovac MJ, Kargul GJ, Lim MK, Cui Y, Sano Y, Tanaka T, Liang Y, Mason S, Paonessa PD, Sauls AD, DePalma GE, Sharara R, Rowe LB, Eppig J, Morrell C, Doi H. Large-scale cDNA analysis reveals phased gene expression patterns during preimplantation mouse development. Development. 2000;127:1737–1749. PubMed

Durkin ME, Avner MR, Huh CG, Yuan BZ, Thorgeirsson SS, Popescu NC. DLC-1, a Rho GTPase-activating protein with tumor suppressor function, is essential for embryonic development. FEBS Lett. 2005;579:1191–1196. doi: 10.1016/j.febslet.2004.12.090. PubMed DOI

Wang D, Lemon WJ, You M. Linkage disequilibrium mapping of novel lung tumor susceptibility quantitative trait loci in mice. Oncogene. 2002;21:6858–6865. doi: 10.1038/sj.onc.1205886. PubMed DOI

Genotype-driven sensitivity of mice to tick-borne encephalitis virus correlates with differential host responses in peripheral macrophages and brain

Genetic Influence on Frequencies of Myeloid-Derived Cell Subpopulations in Mouse

A novel locus on mouse chromosome 7 that influences survival after infection with tick-borne encephalitis virus

Gene-specific sex effects on eosinophil infiltration in leishmaniasis

Mapping the genes for susceptibility and response to Leishmania tropica in mouse

Mice with different susceptibility to tick-borne encephalitis virus infection show selective neutralizing antibody response and inflammatory reaction in the central nervous system