Article: a PhD thesis.
Transient Tumor Microenvironment Re-Programming by Low-Dose Irradiation Fosters Responsiveness of Advanced Ovarian Cancer to Combinatorial Immunotherapy
Université de Lausanne, Faculté de biologie et médecine
Faculté de biologie et de médecine
Université de Lausanne
Université de Lausanne
The goal of cancer immunotherapy is to harness a patient's immune system to target and destroy malignant cells. Several approaches can be taken including check-point blockade with monoclonal antibodies (mAbs) against cytotoxic T-lymphocyte-associated antigen (CTLA-4) and the programmed cell-death protein-1 (PD1/PDL-1) axis to abrogate the engagement of T cells with inhibitory receptors. Ànother strategy is the adoptive transfer of ex vzvo-expanded tumor infiltrating lymphocytes (TILs) with high-dose interleukin-2, or of T cells that have been gene-engineered with a receptor that targets them specifïcally to the tumor. These therapies have led to remarkable clinical responses, including complété remission, but not for ail tumor-types, and not for ail patients. Previous studies have documented a corrélation between ovarian cancer (OC) patient survival and the degree to which their tumors are infiltrated with T cells, thus marking OC as a promising target for immunotherapy. Early interventions against OC included high-doses of whole abdominal radiotherapy (WART) to directly kill the tumor cells, but due to high patient toxicity and low efficacy, WART has been largely abandoned. Recently, however, a few groups have shown that low dose irradiation (LDI) has profound effects on tumor immunity, including enhanced T cell infiltration, and has the potential to synergize with cancer immunotherapy. Here we have explored the effects of low-dose WART against ID8, an initially slow growing but aggressive murine tumor model that closely resembles human OC. By immunohistoehemistry and Nanostring analysis we observed immune infiltration (CD8+ T cells, antigen presenting cells, T regulatoiy cells etc.) and immune gene régulation, respectively, in LDI treated versus control tumors. Based on the upregulation of druggable immune targets we then rationally developed a combinatorial treatment comprising LDI for TME re-programming, cyclophosphamide to deplete regulatorv T cells, check-point blockade mAbs against both PD-1 and CLTA-4, and agonist mAb targeting CD40 to promote antigen presenting cell activity. The combination, which was given once per week for 3 weeks, significantly enhanced survival, and deconvolution of the treatment revealed that ail reagents were required for full benefit. Moreover, if LDI was not included, or only applied at the first treatment cycle, ail survival benefit was lost. In vivo depletion assays demonstrated a rôle for both CD8f T cells and NK cells to protection by radio-immunotherapy, and an in vivo blocking assay revealed a critical rôle for transmembrane protein NKG2D, which is found on both cell-types. Finally, the radio-immunotherapy also provided survival benefit against advanced intraperitoneal CT26 colon tumors, with an important drop in survival without LDI. We believe that this work provides critical insight into TME re-programming by LDI, and the application of radio-immunotherapy to patients. A clinical study combining LDI, cyclophosphamide and check-point blockade against both PD1 and CTLA-4, for the treatment of advanced metastatic solid tumors will be conducted.
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