Immunoregulatory mechanisms in the tumor microenvironment and resistance to therapy

Breakthroughs in cancer treatment have come from understanding oncogenic signaling, the tumor ecosystem, and cancer immunobiology. Targeted therapies provide – in some tumor types – remarkably high clinical responses followed, unfortunately, by relapse. In contrast, immunotherapies, especially checkpoint inhibitors, can induce long-lasting responses by activating anti-tumor immunity, albeit only in a subset of patients. These limitations have driven interest in understanding both innate and acquired resistance to therapies.

Our research focuses on unraveling the complexity of the interplay between cancer and stromal cells in the tumor microenvironment (TME), as tumors erect multiple barriers to evade immune destruction, resulting in non-responsiveness to treatments. Therefore, we are delving into the roles and regulation of suppressive cell populations to identify vulnerabilities in cancer and stromal cell crosstalk that can be targeted therapeutically. To better understand the microenvironment-mediated mechanisms of therapeutic resistance and recurrence in malignancies, we will investigate acquired and innate resistances associated with alterations in the activation of suppressive populations (i.e., tumor-associated macrophages)  and their effectors to suppress tumor immunity in response to therapies.

Taking advantage of our immunocompetent GEMM models of cancer (melanoma, pancreatic cancer, and glioma) and our collaboration with our clinical partners, we aim to

1) investigate susceptibility and resistance to immunotherapies (innate and acquired),

2) elucidate cancer immunosuppressive barriers and the means to transform them into components that elicit tumor immunity, and

3) dissect T cell activity and dysfunction.

The Tichet group is supported by the LOEWE Center Frankfurt Cancer Institute (FCI) funded by the Hessian Ministry of Higher Education, Research and the Arts.