A multi-omics approach to characterize the mechanistic underpinnings of cancer immunoprevention efficacy exerted by a novel CD137 agonist

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Presentation Time: 05:30 PM - 05:45 PM
Abstract ID: 5626 - B

Presenting Author:
Feyza N Arguc , Graduate Student at Univ. of Missouri, Columbia

Abstract:

An oligomeric recombinant form of 4-1BBL, SA-4-1BBL, as a single agent invokes an immune surveillance mechanism with a long duration (>14 weeks) that protects against various cancer types and agonist Abs to 4-1BB lack such efficacy. We herein applied a multi-omics approach to elucidate the mechanistic underlying of immunoprevention. C57BL/6 mice were pretreated s.c. with SA-4-1BBL or an agonistic Ab twice 2 weeks apart followed by challenge with the TC-1 cancer cells two weeks later. Flow cytometry and bulk RNA-seq were performed on treatment site-draining LNs 3 days after the second SA-4-1BBL treatment. Pretreatment with SA-4-1BBL prevented tumor growth in 60% of mice, while the remaining animals exhibited slow progression of the tumor.  In marked contrast, all mice treated with PBS or Ab expired from tumor burden within 30 days. Deep immunophenotyping showed significantly increased numbers of NK, NKT, CD4⁺ T, and various myeloid cell subsets in the SA-4-1BBL cohort as compared to Ab and PBS groups. Bulk RNA-seq analysis identified 250 differentially expressed genes unique to the SA-4-1BBL group that belonged to innate immune, complement, cytokine/chemokine, and PPAR pathways.  These results demonstrate that SA-4-1BBL as a single agent invokes an immune surveillance mechanism by altering various immune pathways.   Further elucidation and confirmation of the pathways that exert protection against cancer hold significant potential for cancer immunoprevention.