ASH 2025: Sasp-Driven Immune Evasion Defines a Novel African Ancestry-Associated DLBCL Subtype with Distinctive Molecular and Immune Vulnerabilities

African Americans with diffuse large B-cell lymphoma (DLBCL) are susceptible to cancer development at an earlier age and worse survival outcomes. Genetics are thought to play a role in these disparities, as individuals with African ancestry (from both America and Malawi) have been found to have an increased frequency of genetic mutations associated with DNA damage and genomic instability than their European counterparts.

In the present study, Foundation Postdoctoral Fellowship grantee Sanket Shah, MD of Weill Cornell Medicine described the effects of this mutation profile in a mouse model of DLBCL.

The investigators found that there was enrichment of exhausted (or dysfunctional) T cells in the African ancestry DLBCL mice. They also found high rates of genomic instability relative to control mice, consistent with what is seen in human cells. Genomic instability can lead to senescence in cells, or the loss of their ability to grow and divide; although it is not typically thought of as a characteristic of DLBCL, researchers found high rates of senescence in both mouse models and human cells with the African ancestry mutation profile. Senescence was found to correlate with the enrichment of exhausted T cells, suggesting it may play a role in immune modulation.

To better understand this relationship, investigators examined the growth of cells based on their expression of senescence-associated proteins (SASP+ and SASP-). They found that while SASP+ and SASP- cells grew the same in culture and in immunodeficient mice, when they were transplanted into mice with a fully functioning immune system, only the SASP+ cells could form tumors. These results suggested that senescence is required to evade immune suppression, which the researchers hypothesized was related to T cell exhaustion levels. When exhausted CD4+ T cells were depleted in the mice, lymphoma progression was impaired.

Although checkpoint inhibitors are generally ineffective in DLBCL, the investigators also hypothesized that they may be more effective in the cells with high rates of genomic instability at baseline. Indeed, they found that the DLBCL mice with the African ancestry profile were highly sensitive to checkpoint inhibitor therapy, with prolonged complete remissions. Additional studies of combination therapies targeting specific mutations commonly seen in individuals with African ancestry are currently underway.

The results of this study help to explain differences in outcomes for people with African vs European ancestry. Researchers hope that ongoing research on the use of targeted therapies associated with the distinct DLBCL mutation profile observed in people with African ancestry will help to reveal new treatment options that will improve outcomes in this historically underserved population.

This study also included contributions from Foundation SAB member and Chair-elect Christopher Flowers, MD, MS of The University of Texas MD Anderson Cancer Center; Foundation SAB members Lisa Giulino Roth, MD of Weill Cornell Medicine; and Ari Melnick, MD of Weill Cornell Medicine; and Foundation grantees Michelle Lee, MD, PhD of Winship Cancer Institute of Emory University; Vignesh Shanmugam, MD of Brigham And Women’s Hospital, Inc.; Daniela Magliulo, PhD of Weill Cornell Medicine; Wendy Béguelin, PhD of Weill Cornell Medicine; and Jean Koff, MD, MS of Winship Cancer Institute of Emory University.