Epidermal EGFR Controls Cutaneous Host Defense and Prevents Inflammation

Abstract

The epidermal growth factor receptor (EGFR) plays an important role in tissue homeostasis and tumor progression. However, cancer patients treated with EGFR inhibitors (EGFRIs) frequently develop acneiform skin toxicities, which are a strong predictor of a patient's treatment response. We show that the early inflammatory infiltrate of the skin rash induced by EGFRI is dominated by dendritic cells, macrophages, granulocytes, mast cells, and T cells. EGFRIs induce the expression of chemokines (CCL2, CCL5, CCL27, and CXCL14) in epidermal keratinocytes and impair the production of antimicrobial peptides and skin barrier proteins. Correspondingly, EGFRI-treated keratinocytes facilitate lymphocyte recruitment but show a considerably reduced cytotoxic activity against Staphylococcus aureus. Mice lacking epidermal EGFR (EGFR(Δep)) show a similar phenotype, which is accompanied by chemokine-driven skin inflammation, hair follicle degeneration, decreased host defense, and deficient skin barrier function, as well as early lethality. Skin toxicities were not ameliorated in a Rag2-, MyD88-, and CCL2-deficient background or in mice lacking epidermal Langerhans cells. The skin phenotype was also not rescued in a hairless (hr/hr) background, demonstrating that skin inflammation is not induced by hair follicle degeneration. Treatment with mast cell inhibitors reduced the immigration of T cells, suggesting that mast cells play a role in the EGFRI-mediated skin pathology. Our findings demonstrate that EGFR signaling in keratinocytes regulates key factors involved in skin inflammation, barrier function, and innate host defense, providing insights into the mechanisms underlying EGFRI-induced skin pathologies.

EGFR and NF-κB: partners in cancer

“…They include hair loss, acneiform eruption, paronychia, and xerosis. Mechanistically, these symptoms result from the inflammation-prone response of keratinocytes to early infiltration of macrophages and mast cells into the skin, as well as from an increased percentage of circulating granulocytes and platelets, but decreased percentage of lymphocytes in the plasma [73,74]. The genetic inactivation of EGFR in the epidermis mimics those symptoms, suggesting that EGFR expression maintains skin immune homeostasis [73].…”

“…EGFR-deficient keratinocytes overexpress a variety of chemokines and cytokines (such as IL-1b, TNFa, and IL-6) that are known to be regulated by NF-kB-dependent pathways. However, the genetic inactivation of single proinflammatory pathways (e.g., TNFR1/R2, Myd88) did not reverse the induction and maintenance of the skin phenotype in the EGFR-deficient mouse model [73,74]. Therefore, it is unlikely that targeting NF-kB alone will improve cutaneous toxicity seen with EGFR inhibitors.…”

Generation and characterization of a target-selectively activated antibody against epidermal growth factor receptor with enhanced anti-tumor potency

“…21,22 Although the mechanism underlying the skin toxicities caused by EGFR inhibition was still unclear, studies suggest that EGFR signaling in keratinocytes regulates key factors involved in skin inflammation and innate host defense. 12,23 Therefore, antibodies recognizing a tumor-specific EGFR epitope, such as EGFR VIII, provide the potential to enhance therapeutic specificity. 1 It is noteworthy that a recent study has shown that a novel Probody TM technology platform was able to limit cutaneous side effects in preclinical study.…”

“…[8][9][10] Although EGFR is an attractive target for anticancer therapy, it is widely expressed on normal tissue such as the liver, skin and gastrointestinal tract, which usually causes dose-limiting side-effects and characteristic toxicities in patients treated with anti-EGFR therapy. 2,11,12 Panitumumab is a human IgG2k mAb that binds specifically to EGFR with high affinity, and not to the other ErbB family members. 13,14 Treatment with panitumumab has been associated with low immunogenicity and low risk of hypersensitivity reactions.…”

Preclinical studies of a Pro-antibody-drug conjugate designed to selectively target EGFR-overexpressing tumors with improved therapeutic efficacy

“…7,8 As reviewed by relevant studies, EGFR inhibitors were thought to affect keratinocytes by inducing skin inflammation and innate host defense. 9,10 A proteaseactivated antibody (Pro-antibody) that is inactive in normal tissues and selectively activated by the proteases upregulated in tumor tissues is an attractive approach to reduce side effects caused by target binding in healthy tissues. 11,12 Recently, Desnoyers et al designed a pro-antibody based on cetuximab that improved the safety profile without compromising the pre-clinical efficacy.…”