Assessing the potential of immunotherapy in treating chronic lymphocytic leukemia through meta-analysis.

7531 Background: Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults and has a heterogenous presentation. CLL is known to shape the immune response to survive. Studying these processes will help gauge the potential success of immunotherapy and point to therapeutic targets. Methods: We used our Search, Tag, Analyze, Resource platform to meta-analyze patient samples from Gene Expression Omnibus. We tagged peripheral B cells from 741 CLL patients and peripheral B cell samples from 150 healthy donors as a control. We also tagged and compared B cell samples from 84 CLL progressors to 91 patients with stable CLL. Lastly, we tagged peripheral T cells from 70 CLL patients and T cells from 35 healthy donors as a control. We then analyzed the signature in Ingenuity Pathway Analysis. Results: Analysis of CLL cell samples identified T cell exhaustion signaling as our top canonical pathway. IL2, IL5, and TGFB1 were top upstream regulators. We found upregulation of PDL1, CTLA4, and Lag3, known markers for immunosuppressive B cells. FMOD, which sequesters TGFB, was also upregulated along with molecules that modulate BCR signaling such as MIR155HG. EBF1, required for B cell differentiation, and the co-stimulatory molecule CD80 were downregulated. Analysis of progressing CLL versus stable CLL highlighted metabolic changes. S-adenosyl-L-methionine biosynthesis, methionine degradation to homocysteine, cysteine biosynthesis, and acetate conversion to acetyl-CoA were top canonical pathways. No difference was seen in PDL1, CTLA4, and Lag3 expression but EBF1 was upregulated. Lastly, our T cell analysis demonstrated NFAT in regulation of the immune response as the top canonical pathway. Conclusions: Our results reinforce the promise immunotherapy can have in treatment of CLL and suggests more aggressive cases of CLL are a function of metabolic changes as opposed to differences in immune escape. We also suggest a role of NFAT in T cell exhaustion in the context of CLL.