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

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.

The Hodgkin Lymphoma Immune Microenvironment: Turning Bad News into Good

“…HRS cells release chemokines to attract T cells or some of their subsets, while T cells increase the clonogenic growth of tumor cells and attract more cell populations by releasing other factors [ 20 , 21 ]. This vital relationship is physically manifested by the formation of HRS-T cell aggregates, called rosettes, which are considered to be one of the hallmarks of cHL [ 22 ], in which the reactive T cell compartment is remarkably heterogeneous [ 3 ] and entirely lacking in senescence markers [ 23 ].…”

“…Alternatively, CD8 + T cells use the MHC-I complex to detect antigens and directly kill neoplastic or virus-infected cells. Secondly, T cells can be classified by their differentiation stages, including naive T cells, which have never been exposed to an antigen, central memory (CM) T cells, effector memory (EM) T cells, and terminally differentiated (TEMRA) T cells [ 3 ].…”

“…Observational data favor the general idea that genomic lesions occurring early in the neoplastic HRS clone lead to aberrant activation of signaling pathways and transcription factors [ 3 , 4 , 5 , 6 ], which induces specific secretory profiles of growth factors, chemokines, and cytokines that, together, foster and shape the microenvironment [ 6 , 7 ]. This complex process includes remodeling the stroma and cellular matrix, as well as migration and activation of leukocytes [ 8 ].…”

Angioimmunoblastic T-cell lymphoma combined with Hodgkin’s lymphoma:a case report

“…In the 2008 edition of the 'WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues', RS-like cells were mentioned, for the first time, to be seen in early AITL 12 ; AITL and CHL also have lymph node structure destruction, and plasma cell, tissue cell, and other inflammatory cell infiltration, in addition to a correlation with EBV infection 13 thereby confirming the dependence of AITL and CHL on immunophenotypes only. The immunophenotype of CHL includes CD15+, CD30+, PAX-5 weakly positive, CD3-, CD20-(mainly), CD45-, and CD79a-, which combined with RS cells, help in the diagnosis 14,15 CHL and AITL are two types of lymphoma with extremely different prognoses. While CHL has good prognosis, with a 5-year overall survival (OS) rate > 80% 16 AITL has poor prognosis.…”

O microambiente no linfoma de Hodgkin: um estudo sobre as subpopulações de células T e macrófagos em neoplasias EBV positivas e negativas

“…Neste estudo encontramos a associação da presença do EBV no LHC com estádio mais avançado (III-IV), da mesma forma como demonstrado por Lee et al 181 ; apesar de ter se mostrado relevante em diversos aspectos do LH, a infecção do EBV não influenciou a evolução dos pacientes em outros parâmetros clínicos avaliados neste trabalho, como também observado em outros trabalhos na literatura 202 . Isso diverge do trabalho de Kanakry et al 204 Nesse sentido, ao longo da trajetória deste estudo, uma nova subpopulação de células T citotóxicas foliculares, com perfil imunofenotípico superponível às células T auxiliadoras (CD8 CXCR5+ ICOS+ ) foi identificada em cerca de 7% dos casos de LHC, exibindo características de células disfuncionais, com citotoxicidade reduzida, baixos níveis de secreção de IFN, assim como estimulando a proliferação de células B e produção de Acs in vitro 209,210 . Fenotipicamente, a presença dessas células no LHC está relacionada à arquitetura nodular com centros germinativos hiperplásicos, somente parcialmente infiltrados pelo infiltrado neoplásico adjacente.…”