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Tumor-immune profiling of murine syngeneic tumor models as a framework to guide mechanistic studies and predict therapy response in distinct tumor microenvironments.

ABSTRACT: Mouse syngeneic tumor models are widely used tools to demonstrate activity of novel anti-cancer immunotherapies. Despite their widespread use, a comprehensive view of their tumor-immune compositions and their relevance to human tumors has only begun to emerge. We propose each model possesses a unique tumor-immune infiltrate profile that can be probed with immunotherapies to inform on anti-tumor mechanisms and treatment strategies in human tumors with similar profiles. In support of this endeavor, we characterized the tumor microenvironment of four commonly used models and demonstrate they encompass a range of immunogenicities, from highly immune infiltrated RENCA tumors to poorly infiltrated B16F10 tumors. Tumor cell lines for each model exhibit different intrinsic factors in vitro that likely influence immune infiltration upon subcutaneous implantation. Similarly, solid tumors in vivo for each model are unique, each enriched in distinct features ranging from pathogen response elements to antigen presentation machinery. As RENCA tumors progress in size, all major T cell populations diminish while myeloid-derived suppressor cells become more enriched, possibly driving immune suppression and tumor progression. In CT26 tumors, CD8 T cells paradoxically increase in density yet are restrained as tumor volume increases. Finally, immunotherapy treatment across these different tumor-immune landscapes segregate into responders and non-responders based on features partially dependent on pre-existing immune infiltrates. Overall, these studies provide an important resource to enhance our translation of syngeneic models to human tumors. Future mechanistic studies paired with this resource will help identify responsive patient populations and improve strategies where immunotherapies are predicted to be ineffective.

SUBMITTER: Yu JW

PROVIDER: S-EPMC6214511 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Tumor-immune profiling of murine syngeneic tumor models as a framework to guide mechanistic studies and predict therapy response in distinct tumor microenvironments.

Yu Jong W JW Bhattacharya Sabyasachi S Yanamandra Niranjan N Kilian David D Shi Hong H Yadavilli Sapna S Katlinskaya Yuliya Y Kaczynski Heather H Conner Michael M Benson William W Hahn Ashleigh A Seestaller-Wehr Laura L Bi Meixia M Vitali Nicholas J NJ Tsvetkov Lyuben L Halsey Wendy W Hughes Ashley A Traini Christopher C Zhou Hui H Jing Junping J Lee Tae T Figueroa David J DJ Brett Sara S Hopson Christopher B CB Smothers James F JF Hoos Axel A Srinivasan Roopa R

PloS one 20181102 11

Mouse syngeneic tumor models are widely used tools to demonstrate activity of novel anti-cancer immunotherapies. Despite their widespread use, a comprehensive view of their tumor-immune compositions and their relevance to human tumors has only begun to emerge. We propose each model possesses a unique tumor-immune infiltrate profile that can be probed with immunotherapies to inform on anti-tumor mechanisms and treatment strategies in human tumors with similar profiles. In support of this endeavor ...[more]

PMID: 30388137

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Project description:Murine syngeneic tumor models have been extensively used for cancer research for several decades. These tumor models are very simplistic cancer models, but recent reports have, however, indicated that the different inoculated cancer cells can lead to the formation of very different tumor microenvironments (TMEs). Importantly, these types of tumor models have been instrumental in driving the discovery and development of cancer immunotherapies. In order to gain more knowledge from studies based on syngeneic tumor models it is essential to know in more details the cellular and molecular composition of the TME in the different models. It is also important to know about other parameters such as the mechanical tumor stiffness of the different models. This type of knowledge can be used for the rational selection of tumor models for specific studies and for studying the correlation between different tumor-promoting parameters. Here, we compare the tumor microenvironment (TME) of tumors derived from six different commonly used syngeneic tumor models. Using flow cytometry and transcriptomic analyses we show that strikingly different TMEs are formed by the different cancer cell lines. The differences are reflected as changes in abundance and phenotype of myeloid, lymphoid and stromal cells in the tumors. The gene expression profile of tumors from the different models supported the different cellular composition of the TMEs and indicate that different mechanisms of immune suppression are employed in the different tumor models. Cancer-associated fibroblasts also acquire very different phenotypes in the different tumor models. These differences include differential expression of genes encoding ECM proteins, MMPs, and immunosuppressive factors. In consistence with these observations, the mechanical stiffness of the tumors from different models do not simply correlate to the number of infiltrating CAFs even though collagen produced by stromal cells is an important reason for the increased stiffness of tumors. The gene expression profiles suggest that CAFs can contribute to the formation of an immunosuppressive TME and flow cytometry analyses show CAFs express high levels of PD-L1 in the immunogenic tumor models MC38 and CT26. Comparison with CAF subsets identified in other studies show that CAFs from the different models are skewed towards specific subsets. CAFs from CT26 tumors show similarities to iCAFs and myCAFs, and in athymic mice without infiltrating cytotoxic T cells, CAFs express lower levels of PD-L1 and lower levels of fibroblast activation markers.

Project description:BackgroundImmunotherapy has demonstrated a limited clinical efficacy in approximately 5% of cholangiocarcinoma. The main challenges for an effective immunotherapy response in cholangiocarcinoma arise from the tumor microenvironment, which is poorly understood.MethodsFor a comprehensive analysis of the tumor microenvironment in cholangiocarcinoma, we performed multiplex immunohistochemistry with two 15-marker immune panels and Nanostring assays for a comprehensive analysis of 104 surgically resected cholangiocarcinomas including intrahepatic, hilar, and distal cholangiocarcinoma. We also validated some key findings with a batch integration analysis of published single cell RNA sequencing data.ResultsThis study found that natural killer cells occupy the largest immune cell compartment in cholangiocarcinoma. Granzyme-B+CD8+ effector T cells are significantly associated with better overall survival in both intrahepatic and distal cholangiocarcinoma. Above 85% of intrahepatic cholangiocarcinomas with higher density of PD-1-EOMES-CD8+ effector T cells are associated with long-term survival. However, only the density of PD-1-EOMES-CD8+ T cells in the tumor areas, but not in the peripheries of the tumors, is prognostic. In all three cholangiocarcinoma subtypes, T regulator cells are significantly associated with a poor prognosis; however, M1 and M2 tumor-associated macrophages or PD-L1+ tumor-associated macrophage demonstrate different prognostic values. Combining PD-L1+ M1 or M2, PD-L1- M1 or M2 tumor-associated macrophages, and T regulator cells to subgroup intrahepatic and distal cholangiocarcinoma, the prognosis is significantly better distinguished. Moreover, PD-L1- M2 tumor-associated macrophages is associated with a good prognosis in intrahepatic and distal cholangiocarcinoma, suggesting this subtype of M2 tumor-associated macrophages may be antitumoral. Interestingly, lower densities of various types of immunosuppressive cells are associated with decreased infiltration of effector T cells in distal and hilar cholangiocarcinoma, but not in intrahepatic cholangiocarcinoma. In intrahepatic cholangiocarcinoma, PD-L1+ tumor-associated macrophages exert their immunosuppressive function likely through promoting T cell exhaustion.ConclusionsThis study suggests that the densities of Granzyme-B+CD8+ effector T cells and non-exhausted PD-1-EOMES-CD8+ T cells and the PD-L1 status in the tumor-associated macrophages are prognostic makers in cholangiocarcinomas. The study also supports targeting PD-L1+ tumor-associated macrophages as the immunotherapy for cholangiocarcinoma.

Dataset Information

Tumor-immune profiling of murine syngeneic tumor models as a framework to guide mechanistic studies and predict therapy response in distinct tumor microenvironments.

Publications

Tumor-immune profiling of murine syngeneic tumor models as a framework to guide mechanistic studies and predict therapy response in distinct tumor microenvironments.

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