The Role of the Tumor Microenvironment in Lymphoid Malignancies

Lymphoid cancers represent a heterogeneous group of neoplasms composed of malignant lymphoid cells with variable infiltration by non-neoplastic, mostly immune cells (tumor microenvironment). For some subtypes of lymphoid cancers, the contribution of the microenvironment to the histological appearance is widely recognized and used for pathological classification. Although microenvironment-related biology in lymphoid cancers has been primarily explored in a core set of lymphoma subtypes, the number of entities studied has recently accelerated. The pathogenic evolution of tumor microenvironments and in particular their composition and spatial distribution can be perceived as a complex function of 1) genetic alterations within the malignant cell population, 2) the extent and dependence on the molecular crosstalk involving cyto- and chemokines, and 3) host-specific factors. As a result, three major patterns of microenvironmental architecture can be distinguished termed "Re-education", "Recruitment" and "Effacement". Hodgkin lymphoma can serve as a paradigm for an extensive crosstalk between tumor cells and a quantitatively dominant tumor microenvironment. Importantly, related prognostic implications of tumor microenvironment composition (e.g. macrophage content, representation of T cell subsets) have been extensively studied in this disease. With focus on B cell lymphomas, this talk will highlight the emerging literature about genetic alterations in malignant lymphoma cells that provide the foundation for somatically acquired immune privilege and evasion from immune surveillance. The genomic changes discussed in this talk can be broadly categorized according to the effect that they exert on the tumor microenvironment: 1) Loss or down-regulation of (surface) molecules leading to decreased immunogenicity of tumor cells (e.g. mutations of B2M, CIITA); 2) Increased expression of surface molecules suppressing immune cell function (e.g. structural genomic changes of PDL1, PDL2); 3) Recruitment or induction of a regulatory cellular milieu (e.g. mutations in JAK-STAT and NFκB signaling pathways). The discovery of gene mutations underlying immune privilege, properties of the altered molecules, downstream functional consequences and clinical rationales for therapeutic intervention will be presented in the context of specific lymphoma subtypes. It will be discussed how precise description of genomic and molecular alterations underlying immune privilege might accelerate effective targeting of microenvironment-related biology in the clinical setting. Moreover, the development and clinical implementation of predictive biomarkers will be outlined that harbor the potential to inform on companion diagnostic approaches to accompany therapies such as immunological checkpoint inhibition. Disclosures No relevant conflicts of interest to declare.

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