Microbial Experience Increases Cytotoxicity of Tumor-Infiltrating CD8+ T Cells and Controls Tumor Growth
Location
Hager-Lubbers Exhibition Hall
Description
PURPOSE: Cancer immunotherapy research is conducted with specific pathogen-free (SPF) mice, which most accurately mimic the immune system of a human newborn. This makes translational research challenging, as this mouse model is not an accurate reflection of the adult patients who ultimately receive newly developed treatments. It is necessary to further develop a mouse model that bridges this gap and increases translatability of current cancer immunotherapy research. SUBJECTS: By cohousing SPF mice with regular pet store (PS) mice, we have generated a cohoused (CoH) mouse that reflects the microbial experience of an adult human immune system. METHODS AND MATERIALS: We investigated antigen experience, differentiation, cytotoxicity, and exhaustion of CD8+ T cell populations within the tumor microenvironment of both SPF and CoH mice by injecting them with B16-melanoma. We further investigated how PD-1 expression modulates the efficacy of anti-PD-1/anti-CTLA-4 immunotherapies with a novel in vitro checkpoint blockade assay. ANALYSES: Statistical significance was determined by unpaired t tests with p values < 0.05. RESULTS: CoH mice exhibit significantly increased populations of antigen experienced, differentiated, and cytotoxic CD8+ T cells in blood, spleen, tumor-draining lymph nodes, and tumor. CoH mice also exhibit significantly increased PD-1 expression and slight increases in the efficacy of in vitro anti-PD-1 immunotherapy. Our data also show that CoH mice have superior anti-tumor immunity as evidenced by their significantly lower tumor weights when compared to SPF mice. CONCLUSIONS: Taken together, our results show that microbial experience increases cytotoxicity of tumor-infiltrating CD8+ T cells and controls tumor growth.
Microbial Experience Increases Cytotoxicity of Tumor-Infiltrating CD8+ T Cells and Controls Tumor Growth
Hager-Lubbers Exhibition Hall
PURPOSE: Cancer immunotherapy research is conducted with specific pathogen-free (SPF) mice, which most accurately mimic the immune system of a human newborn. This makes translational research challenging, as this mouse model is not an accurate reflection of the adult patients who ultimately receive newly developed treatments. It is necessary to further develop a mouse model that bridges this gap and increases translatability of current cancer immunotherapy research. SUBJECTS: By cohousing SPF mice with regular pet store (PS) mice, we have generated a cohoused (CoH) mouse that reflects the microbial experience of an adult human immune system. METHODS AND MATERIALS: We investigated antigen experience, differentiation, cytotoxicity, and exhaustion of CD8+ T cell populations within the tumor microenvironment of both SPF and CoH mice by injecting them with B16-melanoma. We further investigated how PD-1 expression modulates the efficacy of anti-PD-1/anti-CTLA-4 immunotherapies with a novel in vitro checkpoint blockade assay. ANALYSES: Statistical significance was determined by unpaired t tests with p values < 0.05. RESULTS: CoH mice exhibit significantly increased populations of antigen experienced, differentiated, and cytotoxic CD8+ T cells in blood, spleen, tumor-draining lymph nodes, and tumor. CoH mice also exhibit significantly increased PD-1 expression and slight increases in the efficacy of in vitro anti-PD-1 immunotherapy. Our data also show that CoH mice have superior anti-tumor immunity as evidenced by their significantly lower tumor weights when compared to SPF mice. CONCLUSIONS: Taken together, our results show that microbial experience increases cytotoxicity of tumor-infiltrating CD8+ T cells and controls tumor growth.