Monocyte-directed targeting of VEGFA in the melanoma microenvironment

Abstract

Abstract VEGFA plays a critical role in the immunosuppressive cancer response and related immunotherapy resistance. Combined with immune checkpoint inhibitors (ICI) such as those against CTLA-4 and PD-L1, anti-VEGFA agents have demonstrated early clinical success in metastatic melanoma and renal cell carcinomas. To overcome toxicity limitations, thereby opening a wider therapeutic window, VEGFA should be targeted near its production source. Recently, localized co-targeting of TGFβ, an immunosuppressive factor, near CD4+ T cells through bispecific “trap” antibodies have demonstrated robust pre-clinical success. Thus, we assert the superiority of a bispecific antibody guiding a “trap” for VEGFA to its cellular source over global anti-VEGFA agents combined with ICIs. We set out to identify the cell population responsible for secreting VEGFA in the melanoma microenvironment. Upon re-analysis of two existing, independent single cell RNA Sequencing datasets of patient-derived melanoma treated with ICIs, we identified myeloid populations as the main producers of VEGFA. We specifically found a classical monocyte population (CD14+ FCN1+ S100A8+) to express high levels of VEGFA. Of note, we discovered significantly higher VEGFA expression in monocytes from non-responders versus responders to ICIs. VEGFA-expressing monocytes are localized to the intratumoral environment, as our analysis of PBMC-derived monocytes lacked high VEGFA expression in comparison to those that were tumor-derived. Based on our findings, we propose the design of a bispecific antibody that simultaneously targets VEGFA and CD14 to leverage the synergistic pro-immune effects and toxicity diminishment that result from localized inhibition. Supported by the NIH (R01 CA236910) and Melanoma Research Alliance Young Investigator Award to Willy Hugo.