Resistance of novel mouse strains different in MHC class I and the NKC domain to the development of experimental tumors

Abstract

To elucidate the immunological mechanisms critical for tumor progression, we bred novel mouse strains, different in the NKC and H-2D domains. We used inbreeding to generate hybrids of Balb/c and C57BL/6 of stable H-2Db+d-NK1.1neg and H-2Db-d+NK1.1high phenotypes. We analyzed the growth of three established MHC class I-deficient tumor cell lines: TC-1/A9 tumor (HPV-associated) and B16F10 melanoma, both syngeneic to C57BL/6, and the MCB8 (3-methycholanthrene-induced tumor) syngeneic to Balb/c. Furthermore, we induced colorectal carcinoma by azoxymethane-DSS treatment to test the susceptibility to chemically-induced primary cancer. We found that the novel strains spontaneously regressed the tumor transplants syngeneic to both Balb/c (MCB8) and C57BL/6 (B16F10 and TC-1/A9) mice. The H2-Db+d-NK1.1neg, but not the H2-Db-d+NK1.1high strain was also highly resistant to chemically-induced colorectal cancer in comparison to the parental mice. The immune changes during TC-1/A9 cancer development involved an increase of the NK cell distribution in the peripheral blood and spleen along with higher expression of NKG2D activation antigen; this was in correlation with the time-dependent rise of cytotoxic activity in comparison to C57BL/6 mice. The TC-1/A9 cancer regression was accompanied by higher proportion of B cells in the spleen and B220+/CD86+ activated antigen-presenting B cells distributed in the lymphoid organs, as well as in the periphery. The changes in the T-cell population were represented mainly by the prevalence of T helper cells reflected by grown CD4/CD8 ratio, most prominent in the b+d-NK1.1neg strain. The results of the present study imply usefulness of the two novel mouse strains as an experimental model for further studies of tumor resistance mechanisms.

The role of immune cell subpopulations in the growth and rejection of TC‑1/A9 tumors in novel mouse strains differing in the H2‑D haplotype and NKC domain

“…Taken together, these results extend the findings published earlier ( 4 ) and provide more detailed information about the changes in the repertoire of immune cells during the development of transplanted TC-1/A9 (H2-Db-d-) tumors in the novel mouse strains differing in the H-2D haplotype and NKC domain. We have demonstrated the important role of NK1.1+ NK cells in the development, growth and rejection of TC.1/A9 tumors and in the regulation of antitumor immunity in general.…”

“…Nkr-p1b and Nkr-p1c BALB gene isoforms of Balb were present in B6-neg mice, whereas Nkr-p1d and Nkr-p1c B6 of B6 origin were present in Balb-high mice; it means that the NKC domain was inherited as a whole. Our previous results also demonstrated the higher relative distribution of CD4+ cells in B6-neg and Balb strains ( 4 ).…”

“…The novel mouse strains were produced by inbreeding (F 30 ) of parental C57BL/6 (H2Db+H2Dd-NK1.1high) and Balb/c (H2Db-H2Dd+NK1.1neg) mice based on the NKC domain gene expression controlled by DNA analysis, H-2D haplotype and NK1.1 by cytometric phenotyping to obtain stable H2-Db-Dd+NK1.1high and H2-Db+Dd-NK1.1neg phenotypes of Balb-high and B6-neg strains, respectively. The homozygosity in the NKC domain (NK1.1 expression) and the H2D haplotype of the novel mouse strains was continuously examined before mating ( 4 ). Breading of mice and all experimental procedures were conducted under SPF conditions in accordance with the European Convention for the Care and Use of Laboratory Animals as approved by the Czech Animal Care and Use Committee.…”

“…We found that inoculation of B6-neg mice with TC-1/A9 tumor cells led to temporal tumor growth up to days 10–12, and then the tumors started to quickly regress. In the Balb-high mice, the period of tumor growth was prolonged to 20 days, similarly to the Balb/c parental strain ( 4 ). In the prophylactic immunization experimental settings using irradiated TC-1/A9 tumor cells in C57BL/6 mice, a remarkable role of NK1.1-positive cells in the development of immunity was observed ( 5 ).…”

Depletion of p21-activated kinase 1 up-regulates the immune system of APC∆14/+ mice and inhibits intestinal tumorigenesis

“…In tumour-bearing mice, an increased number of B cells in the spleen is associated with cancer regression and the presence of B220 + /CD86 + activated antigen-presenting B cells in the lymphoid organs and in the periphery [20]. In an orthotopic murine model of pancreatic cancer, transferring the splenic T cells after short-term blockade of PD1 (programed cell death protein 1) inhibited tumour progression and extended the survival of non-treated tumour-bearing recipient mice [21].…”