Table 1.
Cancer treatment approaches targeting B cells and TLSs based on pre-clinical models.
| Target | Approach | Type of cancer | Works for the axis (in TME) | In vitro or in vivo | Outcome | Ref. |
|---|---|---|---|---|---|---|
| B cells | ||||||
| Antibody induction | Natural anti-sulfated glycosaminogly can antibodies | Gastric, PDAC, CRC, HCC, Lung | Targeting sulfated glycosaminoglycan detected as B cell antigen | In vitro | Suppression of the cancer cell proliferations | [20] |
| Intraperitoneal a L-fucose (Fuc)-enriched Reishi polysaccharide fraction | Lung (LLC) | Induction of B cells activating IgM-mediated cytotoxicity | In vivo | Reduction of tumor growth | [45] | |
| Intratumoral recombinant IL-12 injection | Head and neck SCC | Activation of B cells, and induction of immunoglobulin and IFNg production | Phase lb and Phase II study | Good patient prognosis | [46] | |
| Breg | CD20 specific monoclonal antibody | PDAC | Bregs depletion | In vivo | Reduction of tumor growth | [48] |
| CD20 specific monoclonal antibody | SCC | Enhancement of CTL responses via CCR5-dependent mechanisms | In vivo | Reduction of tumor growth, and improving reactivity to platinum- and Taxol-based chemotherapy | [31] | |
| Rituximab | CRC | Reduction of CD20-positive B cells | In human | Reduction of tumor growth | [49] | |
| Total glucoside of paeony | HCC | Reduction of IL-10-producing B cells | In vivo | Reduction of serum ALT, AST, ALP, and AFP | [50] | |
| Lipoxin A4 | HCC | Reduction of Bregs via inactivation of STAT3, and enhancement of CTLs dephosphorylating STAT3 and ERK | In vivo | Reduction of tumor growth | [51] | |
| Resveratrol | Breast | Reduction of Bregs, leading to low TGF-β via inactivation of ST AT3 | In vivo | Inhibition of lung metastasis | [52] | |
| MK886 | Breast | Reduction of Bregs via inactivation of the 5-lipoxygenase/leukotriene/PPARα pathways | In vivo | Inhibition of lung metastasis | [53] | |
| Ibrutinib | PDAC | Reprogramming macrophages toward a Ml phenotype, and restoration in antitumor activity of CTLs | In vivo | Reduction of tumor growth, and improvement of reactivity to gemcitabine | [32] | |
| Combination of ibrutinib and anti-PD-L1 antibody | Lympho ma, breast, and CRC | Enhancement of antitumor T-cell immune responses | In vivo | Reduction of tumor growth, and improvement of reactivity to chemotherapy | [54] | |
| TLS | ||||||
| Vaccine | GVAX in combination with cyclophosphamide | PDAC | Suppression of Tregs pathway, and enhancement of Th17 cells pathway and PD-1-PD-L1 pathway | In human | Induction of TLSs in 33 of 39 patients 2 weeks after vaccine treatment | [59] |
| Vaccination targeting HPV16 E6/E7 antigens | Cervical dysplasia | Induction of CTLs | In human | Induction of TLSs | [60] | |
| GVAX in combination with cyclophosphamide followed by CRS-207 | Metastatic pancreatic adenocarcinoma | Induction of CTLs | Phase II study | Extending survival for patients | [63] | |
| LT | Recombinant antibody-lymph otoxin-alpha fusion protein | Melanoma | Induction of naive T cells | In vivo | Induction of TLSs | [64] |
| Environ mental factor | Inflammatory diet | CRC | - | In human | Reduction of TLS s, and increasing risk of CRC | [65] |
| Corticosteroid intake | Lung SCC | - | In human | Reductions of TLS density and GC formation | [66] | |
| (chemotherapy) | Lung SCC | - | In human | Reduction of GC formation (TLS density was not changed but the prognostic value of TLS was lost.) | [66] | |
NOTE: CRS-207, live-attenuated Listeria monocytogenes-expressing mesothelin; GVAX, granulocyte-macrophage colony-stimulating factor (GM-CSF) secreting vaccine; inflammatory diet, including red and processed meats, refined grains, carbonated beverages, and some vegetables; Ibrutinib, bruton tyrosine kinase inhibitor; rituximab, a humanized monoclonal antibody directed against human CD20; total glucosides of paeony, showing anti-inflammatory, anti-oxidative, and hepato-protective activities; lipoxin A4, an arachidonic acid-derived anti-inflammatory lipid mediator; resveratrol, a plant-derived polyphenol; MK886, inhibiting leukotriene biosynthesis in leukocytes.
Abbreviations: AFP, alpha fetoprotein; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, glutamic oxalacetic transaminase; Bregs, regulatory B cells; CRC, colorectal cancer; CTLs, cytotoxic T lymphocytes; GC, germinal center; HCC, hepatocellular carcinoma; LLC, lewis lung cancer; LT, lymphotoxin; PD-1, programmed death-1; PDAC, pancreatic ductal adenocarcinoma; PD-L1, programmed death-ligand 1; SCC, squamous carcinomas; TGF-β, transforming growth factor-β; TLS, tertiary lymphoid structure; TME, tumor microenvironment; Th17 cells, T-helper 17 cells; Tregs, regulatory T cells.