Flagship project KQ3

Sensitizing the tumor microenvironment to immune checkpoint therapy trough antibody-based therapeutic combinations in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors, with an extremely poor prognosis, and there is still an unmet need in clinical practice. Like other tumors, inter and intratumoral heterogeneity is one major hurdle to the discovery of new treatments in PDAC. This tumoral and stromal phenotypic heterogeneity is presumably one of the explanations for the failure to improve outcome of many clinical trials evaluating combined chemotherapies, targeted therapies or immunotherapies. Considering that PDAC is characterized by an extremely low ratio of neoplastic to stromal tissue (less than 20%), stroma is a likely major determinant of tumor response to therapy. Cancer-associated fibroblasts (CAF), which are major stromal components, constitute a heterogeneous population and display phenotypical differences (pro or anti tumoral). Immune and stromal cells produce mediators that further induce a highly immunosuppressive environment in PDAC. Macrophages (type 2), myeloid-derived suppressor cells and regulatory T cells are mainly present in tumors with a very low infiltration of T lymphocytes. This cellular context explains the failure of clinical trials evaluated the efficiency of anti-PD-L1 or CTLA4 in PDAC. Thus, there is a need to understand the role of each component of this complex microenvironment in the resistance to treatments and to develop new therapeutic combined strategies to overcome this resistance.

The general objective of this project is to set up mAb-based combinatorial approaches to firing up the microenvironment and obtain higher response rates to immunotherapy in pancreatic cancer.

  • The first part of this project will be to develop an optimized 3D in vitro spheroid model that closely recapitulate the complex cancer-stroma pathophysiological feature found in the pancreatic natural tumor microenvironment. Spheroids composed of tumor cells, CAF and immune cells, will be first characterized using cytometry, imaging technology and immunohistochemistry .
    In parallel, organoids will be developed using primary cells from clinical samples thanks to collaborations with clinicians of ICM (Montpellier Institute for Cancerology) and the organoid platform of Montpellier. CAF and immune cells coming from the same patients will be used to reconstitute the stroma.
  • The second objective will be to use the spheroids and organoids to study mAb-based anti-tumoral effects in combination with conventional chemo- or radio-therapy or with the metabolic drug metformin.
    Three characterized mAbs targeting respectively 3 different targets expressed in the tumor microenvironment (NRG1 as a ligand of HER3, Axl as a receptor and cathepsin-D as a soluble factor) have been selected. The best combinatorial approach will be selected.
  • The third objective will be to use the best combinatorial approach in PDAC mouse syngeneic models in vivo to evaluate the sensitization to anti-PD-1 immunotherapy.

Teams involved in the project:

Objectives of the project:

This project will allow to generate a spheroid model to better understand the interactions between cells of the tumor microenvironment upon administration of mAb-based combinations. This in vitro model will be validated using pancreatic murine tumor and human cell lines, and could be extended to other tumor models. By the analysis of antineoplastic, immunomodulatory and metabolic effects, the spheroid model will allow a large screening of mAb-based combinatorial approaches before in vivo validation of the increased response rate to anti-immune checkpoint therapy.

This project will lead to develop:

  • A new heterotypic in vitro spheroid model for PDAC that will be extended further to other tumor models
  • A consolidated network of expertise to address PDAC using combined antibody therapy for the LabEx MAbImprove
  • Efficient novel therapies targeting different cell subtypes by combination of new monoclonal antibodies in PDAC