How the Tumor Microenvironment Affects DLBCL Prognosis, Treatment

More effective targeted therapeutic regimens could emerge for patients with diffuse large B-cell lymphoma (DLBCL)if researchers utilize cell of origin (COO) combined with tumor microenvironment (TME) to create better risk stratification and prognostication, according to authors of a review article in Chinese Clinical Oncology.¹ A comprehensive review of the most recent achievements in the TME/DLBCL field has not been previously undertaken, the authors said.

Authors of this analysis note that ongoing study of the tumor microenvironment in DLBCL could result in treatments that are more personalized| Image Credit: xb100-stock.adobe.com

DLBCL being heterogeneous in terms of TME composition and genetics has definite prognostic and therapeutic implications. Currently, however, most cases (excepting primary nervous system tumors) are treated with the same kinds of regimens, the team stated.^2,3 Evaluating the TME with immunohistochemical or molecular methods, along with classifying tumors by COO, could lead to more comprehensive and individualized DLBCL treatments that target different tumorigenesis pathways, declared the researchers.

They discussed research updates on the cellular markers and genetics of components of the TME in DLBCL—endothelial cells, myofibroblasts, mast cells, lymphocytes, and macrophages—that most influence tumor behavior and patients’ responses to treatment, focusing on how each component interacts biologically and has “crosstalk” with DLBCL tumor cells. Forty-seven articles in the literature published since 2006—most in the last decade—fit their parameters.

Endothelial cells play an important role in angiogenesis—the formation of new blood vessels. A tumor’s blood vessels differ significantly from normal ones. However, “follow-up of patients treated with anti-angiogenic agents such as anti–VEGF-A antibodies, bevacizumab, and R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride vincristine sulfate (Oncovin), prednisone] has shown that increased vascularity in DLBCL patients may have only minor importance for the disease course.”

Myofibroblasts are stromal cells that play an integral role in lymphoma TME interactions. Overall, higher myofibroblast density is present in tumors that are associated with better outcomes, said the researchers, and the results of one particular gene-expression profiling study showed that “the higher expression of myofibroblast, [dendritic cells], and CD4+ T-cell–related genes was correlated with better outcomes in DLBCL.”

Mast cells may have angiogenic potential in DLBCL, noted the authors, but different studies have had contrasting results. For example, in one study, a greater number of mast cells predicted better lymphoma-specific survival in DLBCL, but in another, patients with higher levels of tryptase, a serine proteinase secreted by mast cells, had suboptimal response to R-CHOP compared with patients who had recovered completely.

Lymphocytes have a key role in tumor immune evasion, the authors said. In general, the “high proportion of inhibitory T cells translates to unfavorable survival in DLBCL. On the other hand, T cells themselves have a defensive mechanism by providing diverse receptors which can confuse tumor cells. TMEs of aggressive B-cell tumors have been shown to contain less diverse T-cell receptors.”

Tumor-associated macrophages (TAMs)have negative prognostic effects in DLBCL. According to the authors, one reason is that M2 TAMs “can suppress T-cell proliferation, and also directly remodel the extracellular matrix in DLBCL, leading to increased angiogenesis”—meaning tumor cells are supported by new blood supplies.

Two signatures, overall. The gene expression patterns of TME in DLBCL branch into a pair of distinct signatures, the authors posit. The stromal-1 signature is marked by the TME’s high expression of extracellular matrix elements (ie, osteonectin, collagen, laminin, fibronectin, thrombospondin, connective-tissue growth factor, remodeling proteins), and the stromal-2 signature is highly vascularized, characterized by high expression of endothelial cell markers, VEGF receptor, endothelial tyrosine kinase, components of caveolae, and genes expressed in adipocytes, like RBP4 and ADIPOQ.

Hopefully, increased understanding of emergent molecular alterations will lead to translational discoveries that benefit patients with aggressive B-cell lymphomas like DLBCL, the authors concluded.

References

1. Rastegar S, Kallen M, Suster DI. Updates in the role of the tumor microenvironment cellular crosstalk and genetic signatures in diffuse large B-cell lymphoma: a narrative review. Chin Clin Oncol. Published online May 11, 2024.doi:10.21037/cco-23-124

2. Höpken UE, Rehm A. Targeting the tumor microenvironment of leukemia and lymphoma. Trends Cancer. 2019;5(6):351-364. doi:10.1016/j.trecan.2019.05.001

3. Liang XJ, Fu RY, Wang HN, et al. An immune-related prognostic classifier is associated with diffuse large B cell lymphoma microenvironment. J Immunol Res. 2021;2021:5564568. doi:10.1155/2021/5564568