The ability of immunomodulatory imide drugs (IMiDs) to inhibit the polarization of T helper cells towards Th2 phenotype depends on cereblon

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B609
Abstract ID: 5061

Presenting Author:
Pratik P Vikhe , Scientist at Dana-Farber Cancer Inst.

Abstract:

IMiDs are small molecules that can modulate the immune system and cellular process by targeting proteins for degradation. IMiDs hijack the CRL4(CRBN) E3 ligase to ubiquitinate and degrade their neosubstrate, IKZF1 and IKZF3, among others. Thalidomide, Lenalidomide, Pomalidomide, as well as the second generation Iberdomide and Avadomide are current IMiDs used in the clinic. In this study, using 13-plex cytokine profiling, we assessed the ability of these five IMiDs to modulate T helper (Th) cell polarization. Most IMiDs polarize the Th cells towards the Th1 phenotype and inhibited Th2, among these Iberdomide, followed by Avadomide, were the most potent. To confirm that these effects are on-mechanism, we used a VHL-based CRBN-PROTAC, 14a, to degrade cereblon (CRBN). While it had not substantial effect on Th cell polarization, pre-treatment of Th cells with 14a rescued the degradation of neosubstrates and cytokine response stimulated by Iberdomide, with the exception of IL-9 levels, indicating a CRBN-independent effect. Pertaining to the significance of these IMiD drugs that are currently used for cancer and proposed for treating autoimmune diseases, this study shows that these small molecules can program T helper cells independent of influence from other immune cells.