Abstract IA001: Deconvoluting the tumor microenvironment to enhance immunotherapy

Abstract

Abstract Cancer evolution to metastasis (the metastatic cascade) involves not only the acquisition of mutations or epigenetic modifications in oncogenes and tumor suppressor gene but also an interplay with the surrounding tumor microenvironment (TME). The TME promotes every step of the metastatic cascade. In this TME immune cells of both the acquired and innate system are highly represented and generally these act in a pro-tumoral fashion or are inert. Much work has been performed on primary tumors and studies of metastasis have lagged behind despite the fact that ~90% of deaths from solid tumors are caused by this process. We have addressed this issue using mouse models of breast cancer lung and bone metastasis. Our studies have particularly focussed upon metastasis associated macrophages (MAMs) that are distinct from the tumor associated macrophages in primary tumors. We have shown that MAMs and their progenitors promote metastatic seeding and persistent growing in both organs. In the lung particularly we have described complex signalling pathways including the regulation of recruitment of classical monocytes to the metastatic site and stages of MAM differentiation form these monocytes. Our data show not only direct pro-tumoral effects of these cells on tumor cells such as conferring survival signals but also indirect ones via suppression of tumor cell cytotoxic T and NK cell activity (Kitamura et al., 2017; Kitamura et al., 2019; Ma et al., 2020). In parallel we have profiled TAMs in primary human breast and endometrial cancers and shown that they are different from circulating monocytes but surprisingly, are also different from each other. Further bioinformatic analysis and multiplex immunohistochemistry using breast cancer data sets shows that TAM signatures can be derived that predict poor disease specific overall survival and disease sub-classes. These TAMs have many different subtypes within a tumor and thus may play independent roles including anti-tumoral roles particularly in the face of immunotherapy. Exploiting these possibilities for therapy will be discussed (Lopez-Yrigoyen et al., 2020). Kitamura, T., Doughty-Shenton, D., Cassetta, L., Fragkogianni, S., Brownlie, D., Kato, Y., Carragher, N., and Pollard, J.W. (2017). Monocytes Differentiate to Immune Suppressive Precursors of Metastasis-Associated Macrophages in Mouse Models of Metastatic Breast Cancer. Frontiers in immunology 8, 2004. Kitamura, T., Kato, Y., Brownlie, D., Soong, D.Y.H., Sugano, G., Kippen, N., Li, J., Doughty-Shenton, D., Carragher, N., and Pollard, J.W. (2019). Mammary Tumor Cells with High Metastatic Potential Are Hypersensitive to Macrophage-Derived HGF. Cancer immunology research 7, 2052-2064. Lopez-Yrigoyen, M., Cassetta, L., and Pollard, J.W. (2020). Macrophage targeting in cancer. Ann. N. Y. Acad. Sci. Ma, R.Y., Zhang, H., Li, X.F., Zhang, C.B., Selli, C., Tagliavini, G., Lam, A.D., Prost, S., Sims, A.H., Hu, H.Y., et al. (2020). Monocyte-derived macrophages promote breast cancer bone metastasis outgrowth. J. Exp. Med. 217. Citation Format: Jeffrey W. Pollard. Deconvoluting the tumor microenvironment to enhance immunotherapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA001.