Increasing knowledge of mutations and signaling proteins in diffuse large B-cell lymphoma (DLBCL) offer prognostic and therapeutic advantages, according to a review of recent findings.
Diffuse large B-cell lymphoma (DLBCL) has a complicated development pattern that is based on genetic alterations of tumor cells, the tumor microenvironment (TME), and tumor cell ability to evade attack by the immune system; however, recent insights into genetic alterations have given rise to the development of promising immunotherapeutic strategies, including CD47 blockades, according to a review article.
CD47 is an immunoglobulin expressed on many tumor cells that acts as a “don’t eat me” signal to the specialized cells known as macrophages that serve to absorb and destroy harmful bacteria and other organisms in the body through the process of phagocytosis.
Recently identified genetic mutations affect engulfment of DLBCL cells by macrophages, providing insights for future therapeutic strategies, according to the article’s author, Daisuke Ennishi, of the British Columbia Cancer Centre for Lymphoid Cancer, in Canada.
The author noted DLBCL is the most common malignant lymphoma, and that altered immune recognition “is deeply involved in tumor development and progression in DLBCL.” For example, reduced expression of major histocompatibility complex proteins resulting from genetic mutations plays “a key role in the immune escape of DLBCL,” the author wrote, further observing that the host immune system is, therefore, an attractive therapeutic target in DLBCL.
The Role of the TME in Immune Escape
Ennishi cited large-scale genetic analyses that established new molecular classifications of DLBCL based on genetic abnormalities associated with prognosis. The identification of these genetic subtypes “can serve as a foothold for personalized medicine for DLBCL,” he wrote. However, the clinical implications of these genetic classifications on future immunotherapies may be limited because “the correlation between the genetic subtypes and TME composition remains unclear.”
According to the author, features of the TME differ between lymphoma types, and notably, “in DLBCL, disrupted cross talk between lymphoma cells and the microenvironment plays a role in the ability of lymphoma cells to escape immune surveillance of the host.”
Phagocytosis is induced by exposure to phosphatidylserine (PS), a phospholipid and a component of the cell membrane. It has a role in cell cycle signaling in relation to apoptosis, or programmed cell death. PS on the cell membrane surface induces phagocytosis, so its presence on the cell surface is an essential element to apoptosis. Investigators have found that TMEM30A (transmembrane protein 30A) moves PS inside the plasma membrane, which thwarts the phagocytosis process of absorption. Ennishi noted that investigators have promoted the elimination of cancer cells in mice by blocking the action of TMEM30A.
These and other findings prompted Ennishi to write that “TMEM30A is one of the main players regulating the ‘eat me’ signal that promotes phagocytosis of macrophages.”
He also addressed TMEM30A gene mutations, which he said occur specifically in aggressive B-cell lymphomas. Studies by the author’s research group confirmed that loss of TMEM30A function promotes phagocytosis of DLBCL cells.
Ennishi also cited a study of signal regulatory protein alpha (SIRPα), “another ‘don’t eat me’ signal that suppresses phagocytosis,” and noted that this analysis helped to confirm that TMEM30A can help “predict the therapeutic response to macrophage checkpoint inhibitors.”
In addition, clinical studies have investigated inhibition of either CD47 or SIRPα in cancers including lymphomas. Inhibition of the CD47-SIRPα axis aims to diminish the “don’t eat me” signal, potentially leading to enhanced phagocytosis.
In particular, Ennishi cited a small study that found “significant efficacy” with no severe toxicity using CD47 blockade in combination with rituximab in patients with relapsed and refractory DLBCL or follicular lymphoma with resistance to immune chemotherapy. The author added that a phase II trial seeking to validate these initial findings is ongoing.
According to the author, "recent biological insights regarding immune evasion by lymphomas have enabled the development of multiple promising immunotherapeutic strategies,” including blockade of CD47, and future therapeutic strategies could target TMEM30A function to enhance the “eat me” signal, potentially facilitating recognition and phagocytosis of DLBCL cells by host macrophages.
Ennishi D. The biology of the tumor microenvironment in DLBCL: targeting the "don't eat me" signal. J Clin Exp Hematop. Published online September 10, 2021 doi:10.3960/jslrt.21015