2. Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) represents the most common type of B-NHL in Western countries. The 2016 World Health Organization (WHO) classification of lymphoid malignancies recognises several subtypes characterised by unique clinical and pathological features, including primary DLBCL of the central nervous system (PCNSL), primary cutaneous DLBCL, leg type, T-cell/histiocyte-rich large cell lymphoma, and EBV-positive DLBCL of the elderly. Nevertheless, most cases of DLBCL fall into the “not otherwise specified” (NOS) category [4]^[4].

DLBCL, like other cancers, develops in a complex tissue environment with a high content of malignant and nonmalignant compartments of the disease, as well as extracellular components that constitute the tumour microenvironment (TME). The cellular and molecular features of TME have a profound prognostic impact^[5] [5] and include T-cells, tumour-associated macrophages (TAMs), dendritic cells (DCs), neutrophils, natural killer (NK) cells and stromal cells [6]^[6]. DLBCL harbours a non-inflamed phenotype characterised by lack of immune cell infiltration, which could explain the modest efficacy of immune checkpoint blockade therapy in relapsed/refractory (R/R) DLBCL patients [7]^[7].

3. Primary Mediastinal B-Cell Lymphoma

Primary mediastinal B-cell lymphoma (PMBL) is a rare but aggressive lymphoma of thymic B-cell origin, accounting for 3% of B-NHLs. Although it presents similar histology to DLBCL, the genetic profile of PMBL is distinct and shares many features with classic Hodgkin lymphoma (cHL, see below) ^[8]. Patients are generally not cured after first-line treatment, and, after relapse, autologous stem cell transplantation (ASCT) is usually beneficial. However, relapsed/refractory (R/R) PMBL cases have poor outcomes and are often managed like other forms of DLBCL [9]^[9].

4. Follicular Lymphoma

Follicular lymphoma (FL) is the second most common B-NHL, accounting for 29–35% of cases. It is a neoplasm of germinal centre B-cells, which display rearrangement of immunoglobulin (Ig) heavy and light chain genes and somatic hypermutation and express common germinal centre markers such as BCL6, AID and CD10 [10,11,12]^[10][11][12]. FL generally presents an indolent clinical course, with median overall survival (OS) of more than 15 years [10,13]^[10][13]. However, about 20% of patients relapse during the first 2 years after treatment, and others evolve into transformed-FL (t-FL), a much more aggressive subtype ^[10].

The crosstalk between malignant FL cells and the surrounding cells of their TME is driven by some recurrent genetic events [14]^[14]. FL is strongly regulated by direct interaction with a germinal centre (GC)-like microenvironment, including myeloid cells, follicular helper T-cells (T_FH), and stromal cells, that may orchestrate efficient immune escape mechanisms [15]^[15]. The TME of FL also displays deregulation of the extracellular matrix proteins involved in collagen deposition and organization [16]^[16]. Cancer-associated fibroblasts (CAFs) are another important FL tumour-promoting actor, providing a niche with high levels of factors involved in B-cell activation and the activation/recruitment of some TME components such as TAMs [17]^[17]. The crosstalk between T_FH cells and FL cells is orchestrated by the interaction between antigen-loaded MHC class II molecules and antigen-specific T-cell receptors.

5. Burkitt Lymphoma

Burkitt lymphoma (BL) includes a heterogeneous group of highly aggressive malignancies of intermediate-sized B-cells that may be found infiltrating both nodal or extranodal tissues in a diffuse pattern [18]^[18]. BL is invariably associated with chromosomal translocations that dysregulate the expression of c-MYC, and, consequently, several downstream genes involved in the control of cellular processes such as cell cycle progression and apoptosis [19]^[19]. The malignant cells usually express the B-cell-specific surface markers CD19 and CD20, as well as low-to-intermediate levels of common acute lymphoblastic leukaemia (ALL) antigen (CD10/CALLA) [20]^[20].

The complex interplay between BL cells and the TME also regulates lymphomagenesis and provides new insights for target immunotherapies. Like DLBCL, BL tumours harbour a noninflamed environment with low infiltration of immune cells and are usually resistant to immune checkpoint blockade. One of the hallmarks of the TME in BL tumours is the high content of TAMs which contribute to tumour progression through the secretion of cytokines and chemokines, and the expression of immune checkpoint proteins such as programmed death ligand 1 (PD-L1) [21]^[21]. The crosstalk between tumour cells, TAMs, PD-1 signalling, viral antigens, and T-cells may result in the high prevalence of M2 macrophages in the TME and contribute to the failed immunity of BL patients [22]^[22].

6. Marginal Zone Lymphoma

Marginal zone lymphoma (MZL) originates from memory B-cells at the marginal zone of lymphoid follicles and account for 5–15% of all NHLs [23,24]^[23][24]. Three distinct entities have been described. Splenic (SMZL) and nodal marginal zone lymphoma (NMZL) arise from the follicle marginal zone of the spleen and the lymph nodes, respectively [24,25,26]^[24][25][26]. Extranodal marginal zone lymphoma (EMZL) of the mucosa-associated lymphoid tissue (MALT) is the most common subtype, accounting for about 60% of MZL cases. This entity is strongly associated with chronic inflammation derived from autoimmune disease or infection, such as Helicobacter pylori. Other tumour sites include eyes and ocular adnexa (13%), skin (9%), lungs (9%) and salivary glands (8%) [23,27,28]^[23][27][28]. MZLs mostly have indolent clinical courses, although NMZL has a poorer prognosis than other subtypes [25,26,27]^[25][26][27].

The course of MZL disease is strongly influenced by the TME, and this latter may therefore represent a promising strategy for early diagnosis and therapy choice. SMZL cells are supported by immune cells such as mast cells and macrophages, which may be recruited by tumour cells through the secretion of cytokines and chemokines [29]^[29]. The TME components of SMZL can regulate stromal cell proliferation, angiogenesis, extracellular matrix remodelling, and induction of adhesion molecule expression [29]^[29]. The chronic inflammation of MALT lymphomas not only triggers B-cell growth but also recruits T-cells, macrophages and neutrophils to the site of inflammation, which contribute to genetic aberrations, DNA damage and genetic instability of the B-cells during somatic hypermutation and class-switching recombination [30]^[30].

7. Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) originates from B-cells, a proportion of them being antigen-experienced B-cells, in the mantle zone of lymph nodes. MCL is usually diagnosed as a late-stage disease and may be observed in both the gastrointestinal tract and bone marrow [31]^[31]. The diagnosis of MCL is mainly performed by a microscopic evaluation of a biopsy, although the detection of chromosomal translocation t (11:14), with the consequent cyclin D1 expression, is considered the molecular hallmark [32]^[32].

The crosstalk between MCL tumour cells and its microenvironment has a central role in disease expansion [33]^[33]. MCL cells have shown constitutive expression of PD-1 and its ligand PD-L1, which converts it into an interesting candidate for immunotherapy targeting this checkpoint [34]^[34]. Aggressive MCL cases are characterised by a low number of T-cells ^[35] and a high frequency of regulatory T-cells (Treg) [36]^[36]. Moreover, follicular dendritic cells (FDCs) have been shown to support MCL cell survival through a cell–cell interaction mechanism [37]^[37]. Autocrine and paracrine secretion of soluble factors could also have an important role within the MCL TME. Interestingly, the blood of MCL patients contains high levels of several cytokines and chemokines, such as IL-8, CCL3 and CCL4, which are correlated with poor survival [38]^[38].

8. Classical Hodgkin Lymphoma

Classical Hodgkin lymphoma (cHL) is a neoplasm derived from B-cells and is mainly constituted by a small number of neoplastic mononuclear cells, i.e., Hodgkin cells, and multinucleated Reed–Sternberg (HRS) cells. cHL accounts for 15–25% of all lymphomas and represents the most common lymphoma subtype in children and young adults in the Western world. The cell of origin (COO) is nowadays unequivocally considered to be a (post)germinal centre B-cell [39]^[39]. Several genetic alterations, targeting a few pathways, have been identified, but none of them can be considered “dominant”. The affected pathways include NF-κB and JAK-STAT, whose aberrant activation fuel HRS cells with proliferative and antiapoptotic stimuli [40]^[40]. Moreover, the LMP1 protein, encoded by EBV that often latently infects HRS cells, likely contributes to NF-κB signalling since LMP1 mimics constitutively active CD402 ^[41].

Genetic lesions of NF-κB pathway genes largely contribute to aberrant activation of this cascade in a cell-intrinsic manner and/or by amplifying signals from the microenvironment [42]^[42]. In addition, HRS cells are outnumbered by reactive cells in the TME, including T- and B-lymphocytes, eosinophils, macrophages, mast cells, plasma cells and stromal cells [43,44]^[43][44].

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