We used somatic cell nuclear transfer to generate two independent lines of transnuclear mice from CD8 T cells recognizing the endogenous melanoma antigen TRP1. These two lines, while having the same specificity, differ by 100 fold in their affinity for antigen. We previously reported that activated CD8 T cells from either TRP1high or TRP1low mouse lines have anti-tumor activity in vitro and can slow the progression of B16 melanoma in vivo to similar extents, suggesting that TCR affinity is not necessarily correlated with anti-tumor function.
Here we first analyzed the mechanism of tumor control in our TRP1 model. In tumor-bearing mice receiving activated TRP1 cells by adoptive transfer, we examined tumor infiltrates and found 1) an increase in the CD8:Foxp3 ratio; 2) a decrease in myeloid suppressor cells; and 3) greatly increased expression of MHC class I and class II expression by the B16 tumor cells. B16 cells upregulate MHC expression in vitro in response to IFNγ; thus, we hypothesize that MHC expression on B16 cells in mice receiving TRP1 adoptive cell therapy is a signature of IFNγ production in the tumor.
We further used a panel of altered peptide ligands to extend the range of TCR activation potentials in our TRP1 model. One ligand, K8, binds poorly to MHC class I yet stimulates robust proliferation, cytotoxicity and cytokine production from both TRP1high and TRP1low cells. Interestingly, K8-activated TRP1high and TRP1low cells fail to upregulate PD-1 expression. When adoptively transferred into tumor-bearing mice, K8-activated TRP1 cells delayed tumor growth to a similar extent as TRP1 cells activated by the reference peptide, yet mice receiving K8-activated cells had an increased chance of developing long-term memory. We show TRP1 tetramer+ CD44+ CD8+ T cells in K8-treated mice that survived both primary and secondary challenge with B16. Transcriptional profiling of K8 versus reference peptide activated TRP1 cells reveals a transcriptional program associated with anti-tumor immunity.
Citation Format: Paul Tyler, Mariah Servos, Stephanie K. Dougan. Quality of initial activation of CD8 T cells specific for TRP1 determines long-term antitumor immunity. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A067.
- ©2016 American Association for Cancer Research.