Key Determinants Of Immunotherapy Success In Frequently-Used Murine Tumor Models

Cancer immunotherapy uses a patient9s own immune system to recognize and eliminate malignant cells. The potential advantages of this approach over conventional treatments include the systemic trafficking of immune cells to treat primary and metastatic disease, inherent antigen-specificity of adaptive immunity to minimize collateral damage, and the induction of immunological memory to prevent recurrent disease. While many acknowledge the promise of immunotherapy, its translation to the clinic has been slow and only occasionally successful. In the more than 3 decades of experience of our laboratory in developing and testing immunotherapy reagents for cancer, we observed that a given set of reagents can produce complete regressions in some but not all tumor models. We hypothesized that a major contributor to this variability was underlying differences in the immune escape strategies utilized by different tumors. Our hypothesis was supported with data from a series of immunotherapy experiments on a panel of experimental murine solid tumor models. Comprehensive immune profiles were generated for each by measuring tumor infiltrating leukocytes (TIL), immune activation, and immune suppression present in the tumor microenvironment using qRT-PCR, immunohistochemistry staining, and flow cytometry techniques. Key differences emerged amongst models in the extent of immune activation that correlated directly with TIL and immunosuppression. From these data, it appears that some tumors are more “visible” to the immune system and have active countermeasures to survive, while others use immune evasion strategies to persist in the host. To classify tumor models along this spectrum, ten immune-related genes and cell markers showing significant change across the models were selected to generate an immunogenicity score for each model: CD40, 41BBL, OX40L, CD80, CD86, CD11c, CD45, BM-2 (PMN marker), Granzyme B, and CD8. Importantly, we observed that MHC class I mouse equivalent H2-D correlated with this immunogenicity level for each tumor. Secondly, Treg and MDSC were measured in the tumor microenvironment and draining lymphoid tissues using immunohistochemical and flow cytometry techniques to determine the dominant suppressor cell population(s) present. Immunotherapy regimens were then developed to match each tumor model using immunogenicity to indicate the level of immune stimulation needed and suppressor cell component to indicate targets for reversing tumor tolerance. These regimens were used to treat established solid tumors in mice and demonstrated that two features of a tumor9s immune profile, namely immunogenicity level and dominant suppressor cell component, are the key determinants of immunotherapy success in vivo. Viewed in this way, the tumor/host relationship becomes the overriding feature for determining optimal treatment for patients based upon immune profiling data obtained at the time of biopsy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1553. doi:1538-7445.AM2012-1553