Control of lymphocyte infiltration of lung tumors in mice by host's genes: mapping of four Lynf (lymphocyte infiltration) loci

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 x OcB-9) F(2) 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.

Fig. 1

Different degrees of lymphocyte infiltration in mouse lung tumors. a Score 0.5; b 800× magnification of the part of the section containing infiltrates, arrow indicates the area with infiltration; c score 1; d score 2; e score 3 ; f no infiltration, score 0; (haematoxylin–eosin, 200× magnification on a, c, d, e and f)

Fig. 2

CD4⁺ and CD8⁺ T lymphocytes infiltrating lung tumors. a Lung tumor with Rat anti-Mouse CD4 antibody and biotin-conjugated Goat anti-Rat IgG antibodies; b consecutive section of the tumor with Rat IgG and biotin-conjugated Goat anti-Rat IgG antibodies; c lung tumor with Rat anti-Mouse CD8 and biotin-conjugated Goat anti-Rat IgG antibodies; d consecutive section of the tumor with Rat IgG and biotin-conjugated Goat anti-Rat IgG antibodies; e spleen section with Mouse anti-Rat CD4 and biotin-conjugated Goat anti-Rat IgG antibodies; f spleen section with Mouse anti-Rat CD8 and biotin-conjugated Goat anti-Rat IgG antibodies; g spleen section with Rat IgG and biotin-conjugated Goat anti-Rat IgG antibodies