The Evolving Knowledge on T and NK Cells in Classic Hodgkin Lymphoma: Insights into Novel Subsets Populating the Immune Microenvironment

SIMPLE SUMMARY: In classic Hodgkin lymphoma, T and NK cells constitute a significant fraction of the reactive microenvironment established by malignant Hodgkin Reed–Sternberg cells. Despite their abundance, T and NK cells remain largely ineffective because of two coordinated levels of immune evasion. The first is based on the acquisition of regulatory properties or exhausted phenotypes that cripple their antitumor activity. The second is represented by their peculiar spatial distribution, with the most immunosuppressive subpopulations lying in close proximity of neoplastic cells. Recent discoveries about the functional role and the spatial orientation of T and NK cells in classic Hodgkin lymphoma are the focus of this review. ABSTRACT: Classic Hodgkin lymphoma (cHL) is a unique lymphoid neoplasm characterized by extensive immune infiltrates surrounding rare malignant Hodgkin Reed–Sternberg (HRS) cells. Different subsets of T and NK cells have long been recognized in the cHL microenvironment, yet their distinct contribution to disease pathogenesis has remained enigmatic. Very recently, novel platforms for high dimensional analysis of immune cells, such as single-cell RNA sequencing and mass cytometry, have revealed unanticipated insights into the composition of T- and NK-cell compartments in cHL. Advances in imaging techniques have better defined specific T-helper subpopulations physically interacting with neoplastic cells. In addition, the identification of novel cytotoxic subsets with an exhausted phenotype, typically enriched in cHL milieu, is shedding light on previously unrecognized immune evasion mechanisms. This review examines the immunological features and the functional properties of T and NK subsets recently identified in the cHL microenvironment, highlighting their pathological interplay with HRS cells. We also discuss how this knowledge can be exploited to predict response to immunotherapy and to design novel strategies to improve PD-1 blockade efficacy.