Abstract P73: The Spatial Organization of Lymphoma Cells with MYC-BCL2 Co-Expression Shapes the Immune Microenvironment and Determines Survival After Chemoimmunotherapy
Shruti Sridhar, Michal Marek Hoppe, Min Liu, Gayatri Kumar, Siddham Jasoria, Aditi Singh, Kanav Gupta, Ziwei Meng, Chartsiam Tipgomut, Patrick Jaynes, Yanfen Peng, Limei Poon, Yen Lin Chee, Susan Swee-Shan Hue, Siok-Bian Ng, Chandramouli Nagarajan, Ong Choon Kiat, Lim Soon Thye, David W. Scott, Xiaofei Ye, Qiang Pan-Hammarström, Vaibhav Rajan, Kasthuri Kannan, Claudio Tripodo, Anand D. JeyasekharanAbstract
Introduction:
MYC and BCL2 co-expression defines double-expressor lymphoma (DEL), a subtype of diffuse large B-cell lymphoma (DLBCL) associated with poor prognosis. However, its clinical utility is limited by inconsistent scoring thresholds and a possible protective role of BCL6. Using multiplexed fluorescent IHC (mfIHC), we previously showed (Hoppe et al., Cancer Discovery 2023) that survival is better predicted by the fraction of tumor cells co-expressing MYC and BCL2 in the absence of BCL6 (M+2+6−), refining DEL classification.
Methods and Results:
In this follow-up study, we assessed the spatial distribution of M+2+6− cells across four independent DLBCL cohorts (n = 449). Geyer’s point process analysis revealed two spatial phenotypes—Clustered and Dispersed. Dispersed M+2+6− cases consistently showed inferior survival (P < 0.05 in 4/4 cohorts), representing the first evidence that spatial architecture of oncogenic subpopulations impacts prognosis. A transcriptional signature derived from dispersed tumors was evaluated in six independent gene expression profiling datasets (n = 4,594), where dispersed-like profiles also correlated with poor survival (P < 0.05 in 4/6 cohorts). We further examined the tumor microenvironment in 152 cases using hyperplex IHC. Dispersed tumors displayed an immune-cold milieu with enriched regulatory and exhausted T cells, higher expression of IDO1 and LAG3, and strong association with the aggressive activated B-cell (ABC) subtype—suggesting that spatial patterning contributes to immune escape. To enable clinical translation, we developed the scDEL Calculator, a machine-learning–based web tool that estimates 2-year relapse risk using routine IHC scores for MYC, BCL2, and BCL6, and calculates the probability of oncogenic co-expression.
Conclusion:
This is the first report, to our knowledge, that the spatial pattern of a tumor subpopulation influences survival and immune microenvironment in cancer. The scDEL Calculator (https://scdel-calc.streamlit.app/) offers a step toward integrating these insights into risk stratification in DLBCL.
Citation Format:
Shruti Sridhar, Michal Marek Hoppe, Min Liu, Gayatri Kumar, Siddham Jasoria, Aditi Singh, Kanav Gupta, Ziwei Meng, Chartsiam Tipgomut, Patrick Jaynes, Yanfen Peng, Limei Poon, Yen Lin Chee, Susan Swee-Shan Hue, Siok-Bian Ng, Chandramouli Nagarajan, Ong Choon Kiat, Lim Soon Thye, David W. Scott, Xiaofei Ye, Qiang Pan-Hammarström, Vaibhav Rajan, Kasthuri Kannan, Claudio Tripodo, Anand D. Jeyasekharan. The Spatial Organization of Lymphoma Cells with MYC-BCL2 Co-Expression Shapes the Immune Microenvironment and Determines Survival After Chemoimmunotherapy [abstract]. In: Proceedings of Frontiers in Cancer Science 2025; 2025 Nov 5-7; Singapore. Philadelphia (PA): AACR; Cancer Res 2026;86(13_Suppl):Abstract nr P73.