Specifically, follicular lymphoma (FL) also requires the supporting structures of the follicular architecture to maintain its survival; the need for these structures is lost in the process of transformation to overt DLBCL, as shown by a lack of dependence on Gα13-dependent signaling [14, 15]. FL is rich in T-cells, constituting up to 50% of the total cell count. Among them, follicular helper T (Tfh) cells, a CD4⁺ T cell subset of recently defined functional entities, plays a major role [16, 17]. Tfh cells provide vital survival signals for FL cells as they do for non-neoplastic germinal center cells by secreting various effector cytokines, including IL-2 and interferon-γ [18]. Stromal cells, such as cancer-associated fibroblasts, secrete several chemokines, such as CXCL12 and CXCL13, which are required for trafficking and retention of various immune cells [19, 20]. Macrophages also promote the growth and survival of FL tumor cells via the CD40 axis [21] and can activate the B-cell receptor functionally [22]. Conversely, FL tumor cells exploit immune escape and immune silencing mechanisms to foster their survival; although not expressing PD-L1 themselves, increased numbers of PD-L1-expressing macrophages and PD1⁺ CD4⁺ and CD8⁺ T cells are noted in FL [23]. The induction and promotion of Tfh cells also helps to create an immunosuppressive milieu in addition to providing growth stimulation and survival signals for FL cells, as mentioned above [18]. Furthermore, Tfh cells induce the migration of regulatory T (Treg) cells, further promoting the silencing and attenuation of the immune system [24]. FOXP3⁺ CD4⁺ Treg cells are known to have a negative prognostic impact and at a higher risk of transformation in FL, which is explained by their immunosuppressive abilities [25]. They not only act on their own but also cooperate with M2 macrophages present in the TME. The complexity of the importance and predictive value of the TME in FL is further complicated by the impact of different therapeutic approaches. The addition of rituximab to therapy seems to neutralize the negative prognostic role of macrophages [26].

In diffuse large B-cell lymphoma (DLBCL), little is known about the interaction between lymphoma cells and cellular components of the TME. Activation of the B-cell receptor in DLBCL is mainly due to mutations in MYD88, CD79B, BCL10, CARD11, CD79A and; other mechanisms of tumor promotion are active, such as activation of JAK-STAT signaling due to SOCS1 and STAT6 mutations, and immune escape due to B2M, CIITA, CD58, CREBBP, and EP300 mutations, such that DLBCL cells seem to be less dependent on the TME [27-29]. However, there is also evidence that some DLBCL subgroups are dependent on TME interactions [28, 29]. CXCR5⁺CD4⁺ T-cells in peripheral circulation support tumor growth and survival in an IL-10 dependent manner [30]. Moreover, DLBCL tumor cells display IL10RA or IL10RB gene amplifications in some aggressive cases, suggesting that the IL-10/IL-10 receptor pathway can be a potential therapeutic target in selected cases of DLBCL [31]. DLBCL cells are also known to regulate their microenvironment by secreting vascular endothelial growth factor (VEGF) and recruiting VEGF-receptor-positive macrophages [32, 33]. Intriguingly, the survival of DLBCL cells in vitro was improved by co-culturing with neutrophils [34]. This is thought to be achieved by the secretion of a proliferation-inducing ligand (APRIL), a ligand of the tumor necrosis factor family [34], physiologically activating several vital proteins related to B-cell survival, such as B-cell maturation antigen. APRIL has also been shown to be a negative prognostic marker for DLBCL [35]. Conversely, DLBCL cells can attract neutrophils by IL-8 secretion and induce the formation of neutrophil extracellular traps [36], which in turn leads to the activation of Toll-like receptor-induced pathways inducing NF-κB, STAT3, and p38 related signaling [36].

The PD-1/PD-L1 axis is currently one of the most popular drug targets for immune checkpoint inhibition and is important in many types of lymphoma. The clinical usefulness of PD-1 blocking monoclonal antibodies has been suggested in several types of non-Hodgkin lymphomas, which are associated with specific genetic alterations leading to overexpression of PD-L1 protein [10, 37]. However, from an immunological perspective, PD-L1 expression can be induced by factors other than genetic overexpression [38]. The expression of PD-1 and PD-L1 is controlled by various types of biological stimuli [39, 40] and represents an immunological potential or degree of exhaustion of T cells responsive to tumor antigens [41-43]. Advances in understanding the mechanisms and immunologic significance underlying PD-1/PD-L1 regulation have led to a more fine-tuned application of checkpoint inhibition therapy for B-cell non-Hodgkin lymphoma.

In particular, CD4⁺CD25^hiFOXP3⁺ Treg cells, a subset of CD4⁺ T cells with potent suppressive activity, have a negative effect on immune surveillance by the TME in B-cell non-Hodgkin lymphoma [25]. Although the drug has not been specifically evaluated in patients with B-cell lymphoma, anti-CCR4 monoclonal antibody (mogamulizumab) successfully decreased the frequency of circulating Treg cells and evoked anti-tumor immune responses in humans [46]. Furthermore, the anti-CCR4 monoclonal antibody showed significant anti-lymphoma clinical activity for cutaneous T-cell lymphoma irrespective of the CCR4 expression level [47], suggesting the significance of Treg cell depletion in the treatment of lymphoma.

Recently, in addition to Treg cell inhibition, several strategies capable of modulating T-cell functions have become available, allowing preclinical and in some cases clinical evaluation of the anti-lymphoma effects of promotion of T-cell co-stimulation. Agonistic monoclonal antibodies directed against the co-stimulatory molecules OX40 (CD134), glucocorticoid-induced TNF-related protein (GITR), and 4-1BB (CD137), have been used to boost antitumor T-cell functions. In preclinical models of lymphoma, T-cell modulation by anti-OX40, -GITR, and -CD137 monoclonal antibodies has been shown to significantly improve the therapeutic efficacy of several immunotherapeutic modalities, including antitumor vaccination and monoclonal antibody therapy [48].

Another straightforward way to redirect immune cells against lymphoma clones within the tumor microenvironment is to modulate NK cell activity to enhance the effector functions of monoclonal antibody drugs. One of the major mechanisms of action of therapeutic monoclonal antibodies in lymphoma is antibody-dependent cell-mediated cytotoxicity (ADCC), whereby NK cells are redirected to the targeted tumor cells through Fc receptors of the antibody drugs. The possibility of further co-stimulation of ADCC cellular mediators via immunomodulatory monoclonal antibodies was hypothesized to synergize with anti-tumor monoclonal antibodies. Since the co-stimulatory molecule 4-1BB is upregulated on NK cells upon Fc receptor engagement [49], agonistic anti-4-1BB monoclonal antibodies have been investigated in combination with anti-lymphoma monoclonal antibodies to increase anti-tumor ADCC. Agonistic anti-4-1BB monoclonal antibodies significantly improved the anti-lymphoma effects of anti-CD20 monoclonal antibodies in preclinical models [49, 50]. Recently, through a first-in-human study, utomilumab in combination with rituximab demonstrated clinical activity in patients with B-cell non-Hodgkin lymphoma [51].

Because of their immunomodulatory properties, thalidomide and its derivatives have also been exploited to target the microenvironment in B-cell non-Hodgkin lymphomas. In addition to their potential to directly interfere with tumor growth and induce apoptosis in tumor cells, these agents promote anti-tumor immunity, including monoclonal antibody-mediated ADCC and anti-angiogenic effects. Lenalidomide has been the most widely investigated drug in this category, showing significant single-agent anti-lymphoma activity in clinical trials [52-54]. However, in combination with standard rituximab-containing chemotherapy, lenalidomide failed to demonstrate a universal benefit against diffuse large B-cell lymphoma [55, 56].