Multiscale Microscopy Of Cellular Immunotherapies
Immunotherapy is an emerging first-line therapy for advanced cancer with the potential to achieve long-lasting regression and cure. Most solid tumors respond to immunotherapy to varying degrees, but the majority of patients experience resistance in tumor subregions followed by relapse. The main effector cells that mediate tumor control are cytotoxic T lymphocytes (CTLs), which kill cancer cells in a cell contact- and antigen-specific manner. However, although CTLs are observed to infiltrate tumors in patients, their ability to control tumor growth is often insufficient. Consequently, immunotherapeutic strategies aim to activate and expand tumor antigen-specific CTLs and further improve their ability to kill within the tumor. Current therapeutic approaches include inhibition of immune checkpoints to silence inhibitory receptors, vaccination with dendritic cells to stimulate endogenous antitumor immune activation and adoptive transfer of patient-derived, genetically modified T cells to enhance the number of tumor-specific cells with strong killing capacity. While each approach has demonstrated experimental and clinical success, no individual or combined strategy has achieved sufficient efficacy in a majority of patients.
Microenvironment-Controlled Immune Function
The clinical success of adoptive T cell transfer in solid tumors appears to be limited by several immunosuppressive barriers imposed by the tumor microenvironment. Transferred CTLs are excluded from tumor lesions or become dysfunctional upon entry into the tumor, interaction with tumor cells is too short-lived to reach full cytotoxic potential, and suppressive immune cells directly or indirectly interfere with CTL activity. Furthermore, in the same patient, distinct microenvironments, such as those at the primary tumor site and metastatic lesions, differ in their response to therapy. In particular, bone metastases are typically resistant to immunotherapy despite successful immune infiltration of the primary lesion. The factors in the bone marrow that inhibit the efficiency of cell-based immunotherapies and the biomarkers that can be used to detect therapeutic failure in a patient at an early stage are only incompletely understood. In ongoing studies, we aim to correlate information from macroscopic imaging (PET/MRI) with cellular and molecular profiling to identify immunosuppressive signatures in bone that can serve as biomarkers for noninvasive therapy monitoring as well as target structures for new therapeutic approaches.