Introduction

Lymphomas mainly comprise Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), representing a heterogeneous group of lymphoproliferative diseases. B-cell lymphomas account for almost 95% of all lymphoma cases [1], among which diffuse large B-cell lymphoma (DLBCL) is the most common subtype, accounting for approximately 30% of all NHL cases [2]. Patients with B-cell lymphomas are usually characterized by lymphadenopathy, extranodal disease or both and present the potential for multiple organ involvement. Therefore, early diagnosis and therapy are essential. With the development of molecular diagnosis techniques, efforts have been made to better classify B-cell lymphoma. However, due to the heterogeneity of this disease, only a few strategies are applied to routine diagnosis and prognosis prediction.

The tumor microenvironment (TME) is a complex network that comprises cellular and noncellular components, forming a physical barrier around tumor cells [3]. Accumulating studies have suggested that the TME components play important roles in the initiation and maintenance of carcinogenesis instead of being bystanders [ECM

ECM represents a protein network surrounding cells, including collagens, proteoglycans, laminin and fibronectin [41]. CAFs are the main source of ECM synthesis and modification [42]. ECM is crucial for tissue homeostasis and normal organ development. Aberrant remodeling of the ECM mediated by collagen deposition or degradation could promote tumor progression. Mechanistically, the remodeled ECM performs various biological functions, including enhancing cell proliferation, increasing cell death resistance and inducing angiogenesis [43, 44].

Other components of TME

Despite the importance of the interactions between the above cells and tumor progression, it is notable that other components of the TME could also influence the fate of tumors. Reprogrammed monocytes could accelerate tumor growth by promoting angiogenesis and remodeling the ECM. Different monocyte subsets can also differentiate into TAMs or DCs, which indirectly participate in tumor progression [45]. Immunosuppressive tumor-infiltrating DCs suppress the antitumor immunity of T cells [46]. These results indicate that the TME is an essential intrinsic portion for the regulation of tumor occurrence, development, invasion and metastasis. Thus, understanding the components of the TME involved in tumorigenesis will contribute to develo** novel therapeutic strategies.

Targeting the TME in B-cell lymphoma

Targeting components of the TME

As mentioned above, the cellular and noncellular components of the TME are involved in tumor progression and the immune response, which provides novel insights for targeted therapies (Fig. 2). Therapeutic strategies are mainly divided into three categories, including depleting existing cells, preventing them from being recruited to tumor sites and reprogramming them into antitumor subtypes [47]. Several promising agents targeting the TME in B-cell lymphoma are summarized in Table 2.

Fig. 2
figure 2

TME targeting strategies to treat B-cell lymphoma. MDSC, TAM (M2), TAN (N2) and Treg inhibit the process of the antitumor immune response through several inhibition pathways and establish an immunosuppressive TME

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Table 2 Clinical trials of agents based on TME cells for B-cell lymphoma treatment
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Targeting TAMs

Several therapeutic strategies targeting TAMs in B-cell lymphoma are currently being investigated. The colony-stimulating factor-1 (CSF-1)/CSF-1 receptor (CSF-1R) signaling pathway is essential for the recruitment, polarization and functional regulation of TAMs [48]. In mantle cell lymphoma (MCL), the secretion of CSF-1 polarizes monocytes into specific CD163+ M2-like TAMs (MϕMCLs), which promotes the proliferation of lymphoma cells. It has been demonstrated that targeting CSF-1R could abrogate MϕMCL-dependent MCL survival [49]. TAMs, also known as nurse-like cells (NLCs), are correlated with the tumorigenesis of chronic lymphocytic leukemia (CLL). Pacritinib, a JAK2/FLT3 inhibitor, was proved to prevent CLL progression by depleting NLCs [50]. Recent studies have verified that CSF-1/CSF-1R blockade improves the efficacy of diverse immunotherapy modalities, such as programmed cell death 1 (PD-1) or cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antagonists [51].

TAMs are highly dependent on the CCL2-CCR2 signaling to mobilize from the bone marrow to the site of inflammation in the TME. CCR2 inhibitors induce the accumulation of monocytes in bone marrow, resulting in reduced numbers of TAMs [51]. Yao et al. reported that CREBBP/EP300 mutations could regulate the FBXW7-NOTCH-CCL2/CSF1, polarizing TAMs to the M2 phenotype and promoting cell proliferation in DLBCL [52].

In addition, the combination of CD47 on the surface of tumor cells and SIRPα on TAMs could induce immune escape. Targeting the CD47-SIRPα axis has shown promising results in hematological malignancies [53]. It was recently demonstrated that the therapeutic effect of CD47 blockade (Hu5F9-G4) combined with rituximab has synergistic activity in an early phase clinical trial of DLBCL and follicular lymphoma (FL) [54].

MiRNAs are endogenous noncoding small RNAs participate in the occurrence and development of human malignancies. Recent studies have clarified that the specific miRNAs are involved in regulating the polarization direction and functional phenotype of TAMs. For example, miR-130, miR-33 and miR-155 can transform TAMs from the M2-like to M1-like phenotype [55, 56].

Targeting MDSCs

Considering the roles of MDSCs in hematological malignancies, it is reasonable to serve MDSCs as a promising target. Signal transducer and activator of transcription 3 (STAT3) and cyclooxygenase 2 (COX2)/PGE2 play a carcinogenic role in a variety of malignant tumors, which participate in the generation, maturation and accumulation of MDSCs [57]. The application of COX2 inhibitors could significantly reduce the abundance of MDSCs and block the function of MDSCs [58]. The results of a large population-based study demonstrated the survival advantages for newly diagnosed DLBCL patients who received COX2 inhibitor [59]. Emerging studies indicate that the phosphatidylinositol 3-kinase (PI3K)/AKT pathway participates in tumorigenesis by facilitating the immunosuppressive state of TME [60]. In HL, previous investigations have revealed that RP6530, a PI3Kδ/γ inhibitor, decreases the percentage of MDSCs, repolarizes TAMs to the M1-like phenotype and downregulates the expression of iNOS, thereby leading to tumor regression [61].

In addition, miRNAs could also affect the function of MDSCs. MiR-30a increases the immunosuppressive function of MDSCs by decreasing SOCS3 mRNA in B-cell lymphoma. Targeting miR-30a could reduce MDSC-mediated immunosuppressive and the number of MDSCs [62]. Li et al. reported that c-Rel, a novel immune checkpoint in MDSCs, participated in various processes, containing development, function and metabolism of MDSCs. Chen and colleagues developed R96A, a c-Rel inhibitor, which can significantly reduce the progression of lymphoma and synergistically enhance the response to anti-PD-1 antibodies [63].

Targeting TANs

Substantial studies have examined various compounds capable of modulating neutrophils [64]. Similar to the cases for TAMs, the combination of SIRPα and CD47 on TANs also mediates the immune escape. In Burkitt lymphoma (BL), KWAR23 (an anti-SIRPα antibody) was found to combine with SIRPα at high affinity and consequently increased the TANs-mediated phagocytosis of BL cells [65].

Inhibition of TANs during tumor progression serves as another effective strategy. In TME, it is implied that the CXCL12/CXCR4 axis plays a complex role in regulating the retention of TANs at inflammatory sites [66]. Emerging studies have revealed that AMD3100, an effective CXCR4 antagonist, could reverse migration and maintain the balance between bone marrow and peripheral blood, thereby inhibiting tumor growth and metastasis [67].

In addition, the CXCR2 axis is proved to be involved in the recruitment of N2 phenotype cells. DLBCL-derived IL-8 interacts with CXCR2 on TANs, forming neutrophil extracellular traps, and further activates the downstream pathway of Toll-like receptor 9 (TLR9) to boost the proliferation and migration of DLBCL cells. Nevertheless, preliminary evidence showed that deoxyribonuclease I, neutrophil elastase inhibitor and blocking CXCR2 or TLR9 could restrain the progression of DLBCL [74]. Although many strategies have been explored, clinical success is still lacking in B-cell lymphoma, which may be related to the heterogeneity and lack specific biomarkers of CAFs [75].

Targeting the ECM

MMPs, enzymes targeting the ECM that cause collagen degradation, could delay the process of tissue regeneration and influence the survival, expansion and progression of tumors [76]. MMP-9, one type of MMPs, has been proved to be involved in the angiogenesis of NHL [77]. In DLBCL, the M2 TAMs could promote tumor progression by inducing cleavage of ECM via legumain [167]. Notably, before nano-immunotherapy becomes a large-scale clinical strategy, researchers need to be cautious about kee** the balance between therapeutic benefit and toxicity risks. Owing to their superparamagnetic properties and high surface-to-volume ratios, the novel nanomaterials are engineered in clinical applications by enhancing the specificity of chemotherapy and controlling the release speed of drugs [168]. The NPs are considered to be an emerging dimension of immunotherapy research.

Other novel technologies

Given that there are numerous tumor-associated mutations and phenotypic variations in tumors, explorations of targeting the TME with genetic therapies and armed oncolytic viruses could promote the tumor response or restrain tumor tolerance [169]. For instance, the hyaluronidase-armed oncolytic virus could degrade the hyaluronan-rich matrix in an attempt to improve virus penetration and inhibit tumor growth in xenograft models. A phase I clinical study also supports that hyaluronidase-armed oncolytic viruses could modulate the TME more pro-inflammatory and alleviate potential toxicity and unwanted cytokine release [170]. TME–targeted therapies in combination with immunotherapies have emerged as a promising approach for cancer treatment. Modified second-generation CAR-T cells could remodel the immunosuppressive TME and revive exhausted T cells, which may further improve clinical efficacy [7].

Conclusions

In this review, we systematically summarize that the composition of the TME plays a vital role in various processes, including the progression, treatment, drug resistance and prognosis of B-cell lymphoma. Targeting TME components is expected to provide novel insights for the precise treatment of B-cell lymphoma. Nevertheless, there are still many unresolved issues, such as drug resistance and the feasibility of drug combination. Further studies are warranted to verify and promote the clinical applications of TME-based targeted therapy. A deep understanding of the contribution of the TME to B-cell lymphomas will help us provide patients with more feasible and effective treatment strategies.