Role of innate CD8+ T cells in cancer

CONSTANZA SAVID FRONTERA; BAEZ NATALIA; RODRIGUEZ GALÁN MARIA CECILIA

Buenos Aires

Congreso; LXVI Reunión Científica Anual de la Sociedad Argentina de Inmunología (SAI); 2018

Sociedad Argentina de Inmunología y Sociedad Argentina (SAI) de Investigación Clinica (SAIC)

Innate CD8+ T cells were discovered about 10 years ago. These cells have particular phenotypic features (CD44hi CD122hi CD49dhi) and exert cytotoxic activity through NKG2D without specific antigen recognition. Innate CD8+ T cells express high levels of the transcription factor Eomesodermin, known to be induced by IL-4, and low expression of T-bet. They rapidly produce IFN after IL-12 and IL-18 stimulation due to constitutive expression of their receptors. Moreover, an antitumor role of innate CD8+ cells has been recently postulated both in mice and human. Our experiments using murine tumor cell lines demonstrate that systemic expression of IL-12+IL-18 (by hydrodynamic injection of its cDNAs) significantly increased the number of innate CD8+ cells in SLO (spleen and lymph nodes) and attenuate tumor growth in OT-I mice compared to control group (injected with an empty cDNA) (p<0.05) suggesting that innate CD8+ T cells could exert tumor growth control in an Ag-independent manner. Accordingly, phenotypic analysis (based on the mentioned markers) demonstrate a significant increase in CD8+CD44hiNKG2D+ innate cells in SLO of OT-I mice (p<0.05). Our data demonstrate that the absence of IL-4 (IL-4 KO mice) did not alter the increased number of innate CD8+ cells in SLO after IL-12+IL-18 expression compared to WT mice demonstrating that generation of these population could be redundantly driven by other signals. Interestingly, IFNgama KO mice show both lower number and lower antitumor effects in OT-I mice after IL-12+IL-18 expression (p<0.05). This result suggests that IFNgama could be involved in both generation and cytotoxic mechanisms of these cells. All together this data suggest that innate CD8+ cells have a critical role in tumor growth control by mechanisms that involve NKG2D and IFNgama and could represent an important antitumor mechanism against cancer cells when TCR specific immune response is bypassed by down-regulation of MHC-I expression in cancer cells.