Adaptive immunosuppressive resistance mechanisms towards antiangiogenic immunotherapies revealed in a pancreatic neuroendocrine tumor (PNET) model

#3885

Introduction: Pancreatic neuroendocrine tumors (PNETs) are mostly indolent but can achieve malignancy. Surgery is the only approved first-line therapy. Kinase inhibitors and radiotherapy for unresectable PNETs are non-curative and targeted therapies are currently lacking for PNETs. However, immune checkpoint inhibitors have created a paradigm shift in cancer therapy with significant increase in overall survival, but are curative only in a subset of patients, partly due to limited T cell infiltration, especially in angiogenic and cold tumors like PNETs. Parallelly, antiangiogenic therapy increases lymphocyte infiltration by normalising the tumor vasculature. Tallying antiangiogenic to immunotherapies (AI) has provided improved survival benefits for patients of advanced RCCs and HCCs, while other cancers like glioblastoma remain highly resistant.

Aim(s): We aim at exploring the efficacy and decipher potential molecular mechanisms of resistance to AI combinations in PNETs.

Materials and methods: We will utilise the endogenous RT2-PNET mouse tumor model. It shows distinct response and relapse phases to inhibitors of angiogenesis (anti-VEGF/R), combined with either immune checkpoint (anti-PD-(L)1, anti-CTLA4) or myeloid immunosuppressive pathway (PI3Kγ/δ) inhibitors, therapies that are currently in clinical trials.

Conference:

Presenting Author:

Authors: John Robbert D, Guyot M, Killian T, Verslype C, Lambrechts D,

Keywords: Pancreatic neuroendocrine tumor, Antiangiogenic immunotherapy, single cell transcriptomics, Immunosuppression,