Combinatorial Reprogramming of Tumor Microenvironments in Cancer Therapy

• Applicant: Professorin Dr. Marie-Nicole Theodoraki
• Subject Area: Hematology, Oncology
• Term: from 2016 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 329569335

Despite aggressive surgery and chemotherapy, the 5-year survival rates for patients with advanced forms of cancer are low. Evidence exists for a tumor-associated immune suppression, which is based on tumor produced tissue protective factors like IL-10, TGF-b, VEGF, IL-6, COX2, which suppress the migration and function of the therapy induced effector immune cells and enhance the recruitment of immune suppressive cells like T-regulatory cells (Treg) and myeloid derived suppressor cells (MDSC). This process is enhanced through expression of Treg and MDSCs-attracting chemokines, which attract MDSCs and Tregs like CCL22, instead of chemokines like CCL5 and CXCL10, which would attract cytotoxic T cells (CTLs) and enhance an anti-tumor-immunity. Intratumoral CTL infiltration predicts improved outcomes and responsiveness to checkpoint blockers. The type, location, and density of tumor-infiltrating lymphocytes are strong predictors of survival, independent of tumor histopathologic and metastatic status. While the number of effector T- cells in many types of cancers have been shown to predict delayed time to cancer recurrence, Tregs are associated with poor tumor response. These findings highlight the potential for modulating tumor infiltrating T-cell densities as well as for modulating the tumor-microenvironment (TME) in favor of anti-cancer immunity.The group of Prof. Dr. Kalinski has recently demonstrated that COX-2 inhibitors, Toll-Like-Receptor (TLR)ligands and type-1 interferons synergize in suppressing the Th2-, MDSC- and Treg- favoring environments in human colorectal, ovarian and prostate cancers and to promote the attraction of the desirable effector- and memory cells. Analogous combinations of factors can also activate local antigen-presenting cells and ex vivo-generated dendritic cells (DCs) to produce activating factors and to selectively promote type-1 immunity, which is desirable in cancer therapy. The unpublished preliminary data of this research group indicate that the same paradigms are also applicable for cervical and head and neck cancers.In order to facilitate optimal ways of incorporating the previously developed combinatorial immunotherapies into comprehensive cancer care, the current proposal aims to evaluate the interplay between the immune system and standard forms of cancer treatment. This project will focus on the development of new immunotherapies of cancer combining DC vaccines with the modulation of TME. Material for research will be colorectal and ovarian cancer tissue as well as HPV-positive tumors from cervical and head-and-neck cancer patients. The advantage of including these multiple tumor types is to maximally benefit from the past experience of this laboratory with colorectal and ovarian cancer and from the available patient material from the ongoing clinical trials, in order to develop new treatments for HPV-positive cancers.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Pawel Kalinski