Abstract
Tumor infiltration by lymphocytes is essential for cell-mediated immune elimination of tumors in experimental systems and in immunotherapy of cancer. Presence of lymphocytes in several human cancers has been associated with a better prognosis. We present evidence that individual propensity to tumor infiltration is genetically controlled. Infiltrating lymphocytes are present in 50% of lung tumors in O20/A mice, but in only 10% of lung tumors in OcB-9/Dem mice. This difference has been consistent in experiments conducted over 8 years in two different animal facilities. To test whether this strain difference is controlled genetically, we analyzed the presence of infiltrating lymphocytes in N-ethyl-N-nitroso-urea (ENU) induced lung tumors in (O20 × OcB-9) F2 hybrids. We mapped four genetic loci, Lynf1 (Lymphocyte infiltration 1), Lynf2, Lynf3, and Lynf4 that significantly modify the presence and intensity of intra-tumoral infiltrates containing CD4+ and CD8+ T lymphocytes. These loci appear to be distinct from the genes encoding the molecules that are presently implicated in lymphocyte infiltration. Our findings open a novel approach for the assessment of individual propensity for tumor infiltration by genotyping the genes of the host that influence this process using DNA from any normal tissue. Such prediction of probability of tumor infiltration in individual cancer patients could help considerably to assess their prognosis and to decide about the application and the type of immunotherapy.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Refrences
Ochsenbein AF et al (2001) Roles of tumour localization, second signals and cross priming in cytotoxic T-cell induction. Nature 411:1058–1064
Wick M, Dubey P, Koeppen H, Siegel CT, Fields PE, Chen L, Bluestone JA, Schreiber H (1997) Antigenic cancer cells grow progressively in immune hosts without evidence for T cell exhaustion or systemic anergy. J Exp Med 186:229–238
Ganss R, Hanahan D (1998) Tumor microenvironment can restrict the effectiveness of activated antitumor lymphocytes. Cancer Res 58:4673–4681
Ganss R, Limmer A, Sacher T, Arnold B, Hammerling GJ (1999) Autoaggression and tumor rejection: it takes more than self-specific T-cell activation. Immunol Rev 169:263–272
Galon J et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964
Diederichsen AC, Hjelmborg JB, Christensen PB, Zeuthen J, Fenger C (2003) Prognostic value of the CD4+/CD8+ ratio of tumour infiltrating lymphocytes in colorectal cancer and HLA-DR expression on tumour cells. Cancer Immunol Immunother 52:423–428
Sato E et al (2005) Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA 102:18538–18543
Clemente CG, Mihm MC Jr., Bufalino R, Zurrida S, Collini P, Cascinelli N (1996) Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer 77:1303–1310
Rosenberg SA (2004) Shedding light on immunotherapy for cancer. N Engl J Med 350:1461–1463
Chen Q, Wang WC, Evans SS (2003) Tumor microvasculature as a barrier to antitumor immunity. Cancer Immunol Immunother 52:670–679
Tripodis N, Demant P (2001) Genetic linkage of nuclear morphology of mouse lung tumors to the Kras-2 locus. Exp Lung Res 27:185–196
Horlings H, Demant P (2005) Lung tumor location and lymphocyte infiltration in mice are genetically determined. Exp Lung Res 31:513–525
Demant P, Hart AA (1986) Recombinant congenic strains—a new tool for analyzing genetic traits determined by more than one gene. Immunogenetics 24:416–422
Stassen AP, Groot PC, Eppig JT, Demant P (1996) Genetic composition of the recombinant congenic strains. Mamm Genome 7:55–58
Groot PC, Moen CJ, Dietrich W, Stoye JP, Lander ES, Demant P (1992) The recombinant congenic strains for analysis of multigenic traits: genetic composition. FASEB J 6:2826–2835
Fijneman RJ, de Vries SS, Jansen RC, Demant P (1996) Complex interactions of new quantitative trait loci, Sluc1, Sluc2, Sluc3, and Sluc4, that influence the susceptibility to lung cancer in the mouse. Nat Genet 14:465–467
Fijneman RJ, van der Valk MA, Demant P (1998) Genetics of quantitative and qualitative aspects of lung tumorigenesis in the mouse: multiple interacting Susceptibility to lung cancer (Sluc) genes with large effects. Exp Lung Res 24:419–436
Tripodis N, Hart AA, Fijneman RJ, Demant P (2001) Complexity of lung cancer modifiers: mapping of thirty genes and twenty-five interactions in half of the mouse genome. J Natl Cancer Inst 93:1484–1491
Tripodis N, Demant P (2003) 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 63:125–131
Vernooy JH, Dentener MA, van Suylen RJ, Buurman WA, Wouters EF (2002) Long-term intratracheal lipopolysaccharide exposure in mice results in chronic lung inflammation and persistent pathology. Am J Respir Cell Mol Biol 26:152–159
NormanGR, StreinerDL (2000) Biostatistics, 2nd edn. BCDecker, Hamilton, p 265
Lander E, Kruglyak L (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11:241–247
Fijneman RJ, Vos M, Berkhof J, Demant P, Kraal G (2004) 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 64:3458–3464
Lipoldova M, Havelkova H, Badalova J, Demant P (2005) 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 114:394–399
von Andrian UH, Mempel TR (2003) Homing and cellular traffic in lymph nodes. Nat Rev Immunol 3:867–878
Butcher EC, Picker LJ (1996) Lymphocyte homing and homeostasis. Science 272:60–66
de Visser KE, Eichten A, Coussens LM (2006) Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 6:24–37
Sinha P, Clements VK, Miller S, Ostrand-Rosenberg S (2005) Tumor immunity: a balancing act between T cell activation, macrophage activation and tumor-induced immune suppression. Cancer Immunol Immunother 54:1137– 1142
Baecher-Allan C, Anderson DE (2006) Immune regulation in tumor-bearing hosts. Curr Opin Immunol 18:214–219
Yamaguchi T, Sakaguchi S (2006) Regulatory T cells in immune surveillance and treatment of cancer. Semin Cancer Biol 16:115–123
Ostrand-Rosenberg S (2005) CD4+ T lymphocytes: a critical component of antitumor immunity. Cancer Invest 23:413–419
Colombo MP, Mantovani A (2005) Targeting myelomonocytic cells to revert inflammation-dependent cancer promotion. Cancer Res 65:9113–9116
Acknowledgments
The authors thank Dr. Bonnie Hylander and Ms. Mary Vaughan for useful comments and discussions of immunohistochemical staining, Dr. Min Hou for discussions on pathology of lung tumors, Ms. Mary Ketcham for assistance with preparation of figures, Mr. Michael J Habitzruther for excellent technical assistance.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kakarlapudi, N., Vernooy, J.H.J., Quan, L. et al. Control of lymphocyte infiltration of lung tumors in mice by host’s genes: mapping of four Lynf (lymphocyte infiltration) loci. Cancer Immunol Immunother 57, 217–225 (2008). https://doi.org/10.1007/s00262-007-0367-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00262-007-0367-3