Review: Advances in the Understanding of DLBCL Immunology Could Spark Novel Therapies

The development of new therapies and new technologies is leading to a better understanding of the immunology of diffuse large B-cell lymphoma (DLBCL), according to a new review.

The article, published in the journal Cancers, outlines the latest insights and their implications for patient care.

Corresponding author Taishi Takahara, MD, PhD, of the Aichi Medical University Hospital, in Japan, and colleagues, said advances in scientists’ understanding of the pathogenesis of the disease have led to new therapies that target intracellular pathways.

“Still, there remains a need to elucidate molecular aspects of the interactions between neoplastic cells and the tumor microenvironment and systemic immune system,” they wrote.

In addition, they said, there is a need to establish better prognostic markers in order to better understand which patients are most likely to benefit from a particular therapy.

The investigators said next-generation sequencing is one of the techniques that has helped expand scientists’ understanding of the disease and of various subtypes of the disease.

“For example, germinal center B-cell-like DLBCL tends to show strong associations with follicular T cells and epigenetic regulation of immune recognition molecules, whereas activated B-cell-like DLBCL shows frequent genetic aberrations affecting the class I major histocompatibility complex,” they wrote.

Takahara and colleagues added that about half of cases of DLBCL involve a lack of cell-surface expression of the class I major histocompatibility complex, which they said is the most prevalent immune-escape mechanism in the cancer type.

The authors said age has also been found to play a significant role in certain types of DLBCL. Specifically, they said age-related immunological deterioration appears to play a role in the pathogenesis of Epstein-Barr virus-positive (EBV+) DLBCL, an aggressive type of DLBCL that has been found to be more common in older patients. They noted that a minority of cases (10%-40%) have dysregulation of programmed death-ligand 1 (PD-L1). However, in cases of EBV+ large B-cell lymphoma (LBCL) in patients under the age of 45, about 77% of patients have PD-L1 overexpression.

“This difference in PD-L1 positivity rate between the two age groups implies that immunosenescence is involved in [the] EBV-infected tumor cell population in elderly patients,” they wrote.

The investigators also discussed subtypes of DLBCL that are located in “immune-privileged sites,” including primary lymphoma of the central nervous system and primary testicular lymphoma. “Immune-privileged sites” are those in which multiple immune-modulating mechanisms exist, the authors said.

“Lymphoma cells in these organs frequently harbor immune escape-associated genetic aberrations, including loss of HLA loci and CD58, and less frequently exhibit PD-L1/L2 copy number alteration and SV [structural variations],” they said.

The investigators concluded that the development of immune-targeting therapies has heightened the importance of understanding the immunological aspects of DLBCL, and they said better methods of examining the cell composition of the tumor microenvironment (TME) have made it possible to better understand how tumor cells interact with immune cells.

“However, there remain many unanswered questions regarding the immunology of DLBCL,” they said, “for example, relating to the TME of extranodal lesions, underlying mechanisms of immunosenescence and lymphomagenesis, immunological diversity according to ethnicity, and the mechanism of pre-tumor cells homing to extranodal cells.”

The authors said these topics should be the subject of further study.

Reference

Takahara T, Nakamura S, Tsuzuki T, Satou A. The immunology of DLBCL. Cancers (Basel). 2023;15(3):835. doi:10.3390/cancers15030835