multiple cancers. After excluding cohorts with <10th percentile of patients, 25 malignancies were evaluated (n=8517). We used odds ratio to model OS with IL-4 expression (high/low, split by median expression value). Multiple testing correction was addressed with highly conservative false discovery rate (FDR) P-value correction to the results of the multivariate hazards models, adjusted for sex, age at diagnosis, and tumor stage. Sensitivity analyses were performed with IL-4R (receptor) and IL-13. We found no significant adverse survival effects with IL-4, IL-4R, or IL-13 expression in the examined cohorts.
IL-4 signaling blockade can lead to enhanced functioning of interferon-gamma (IFNgamma)-producing cells.3 Previous reports reveal extensive anti-tumor effects of IFNgamma in bladder carcinoma, colorectal carcinoma, ovarian carcinoma, and adult T-cell lymphoma.4 IFNgamma can enhance the cytotoxic function of natural killer cells and cytotoxic T cells, increase the antigenicity of tumor cells by up-regulation of major histocompatibility complex class I, induce expression of p21 and p27 molecules to inhibit cell proliferation, and regulate PD-L1 expression on the surface of cancer cells. Furthermore, IFNgamma-deficient mice are more susceptible to spontaneous neoplasms5 and low IFNgamma expression is a poor prognostic factor in ovarian carcinoma and melanoma. Our findings provide further support that dupilumab is unlikely to be associated with an increased malignancy risk. Limitations include that IL-4 expression levels are unlikely to directly correlate with a dupilumab-treatment phenotype. Additionally, we focus on individual expression of single cytokines, while pathways often involve complex changes in the expression of multiple genes. Further prospective work is needed to continually assess the dupilumab safety profile.
DISCLOSURES
JFM was a consultant and/or investigator for Amgen, BMS, AbbVie, Dermavant, Eli Lilly, Novartis, Janssen, UCB, Sanofi, Regeneron, Sun Pharma, Biogen, Pfizer, and Leo Pharma. NK was previously a consultant for BeiGene. JSS was a consultant and/or investigator for Biogen. LPC has no disclosures. CG has no disclosures.
REFERENCES
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- Maloney NJ, Tegtmeyer K, Zhao J, Worswick S. Dupilumab in dermatology: potential for uses beyond atopic dermatitis. J Drugs Dermatol. 2019;18(10):S1545961619P1053X.
- Paludan. Interleukin-4 and Interferon-γ: the quintessence of a mutual antagonistic relationship. Scandinavian Journal of Immunology. 1998;48(5):459-468.
- Miller CH, Maher SG, Young HA. Clinical use of interferon-gamma. Ann N Y Acad Sci. 2009;1182:69-79.
- Dunn GP, Koebel CM, Schreiber RD. Interferons, immunity and cancer immunoediting. Nat Rev Immunol. 2006;6(11):836-848.
AUTHOR CORRESPONDENCE
Joseph F. Merola MD MMSc jfmerola@bwh.harvard.edu
