Abstract 2980: Effects of cetuximab and CD-3379 on cytokine/chemokine balance in the tumor micro-environment (TME) of squamous cell carcinoma of the head and neck (SCCHN)

Abstract

Abstract Background: The Anti-EGFR agent cetuximab has shown promising outcomes and remains to be the only FDA-approved non-immunotherapeutic targeted agent for the treatment of squamous cell carcinoma of the head and neck (SCCHN). There is evidence that immune modulation represents a mechanism by which cetuximab elicits its clinical activity in SCCHN. As resistance inevitably occurs to cetuximab, there is a need to further elucidate the biological mechanisms by which cetuximab affects immune effectors in the tumor microenvironment (TME). We aimed to explore the effect of EGFR inhibition on the cytokine/chemokine balance in the TME. Methods: Three SCCHN cancer cell lines UM-SCC47 (HPV positive), JHU022 (HPV negative), and SCC-1C (HPV negative and resistant to cetuximab) were treated with cetuximab, CD-3379 (a HER3 inhibitor), and their combination. After 48 and/or 72 hours, the supernatants of the treated and untreated cells were collected and subjected to multiplexed immunoassay [Meso Scale Discovery (MSD) U-PLEX Assays] to study the cytokine/chemokine alteration. Changes in immune suppressive chemokines were confirmed by ELISA. A potential effect of a chemokine neutralizing antibody on apoptosis was further evaluated using patient-derived organotypic cancer spheroids (PDOCSs). Results: Our results identified 10 down regulated cytokines/chemokines, including IL6, IL-8, IL-2, IL-12, IL-27, IL-4, IL-5, TGF-β, GM-CSF, and IFN-γ in at least one SCCHN cell line. Three cytokines/chemokines were up regulated, including IL-15, MCP-3, and MCP-1. MCP-1 (CCL2) is a modulator of myeloid-derived suppressor cells (MDSCs). Enhancing MCP-1 by cetuximab and/or CD-3379 in the SCCHN cell lines was confirmed by ELISA. Treating multiple PDOCSs with the same combination along with MCP-1 neutralizing antibody enhanced apoptosis in comparison to cetuximab, CD-3379, or the cetuximab/CD-3379 combination. Conclusions: Our findings suggest that cetuximab in combination with HER3 inhibition affects secretion of cytokines/chemokines which are both immune stimulatory and suppressive in the TME of SCCHN. Alteration of the selected cytokines/chemokines may enhance the clinical activity of EGFR targeting in SCCHN. Citation Format: Dongsheng Wang, Sreenivas Nannapaneni, Gregory B. Lesinski, Dong M. Shin, Nabil F. Saba, Georgia Z. Chen. Effects of cetuximab and CD-3379 on cytokine/chemokine balance in the tumor micro-environment (TME) of squamous cell carcinoma of the head and neck (SCCHN) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2980.