Experimental development of strategies that effectively combine T cell immunotherapy with the inhibition of tumor-promoting signal transduction pathways for the treatment of melanoma
Immunology
Final Report Abstract
In part 1, we characterized the role of the type I IFN system for the functional regulation of adoptively transferred CD8+ cytotoxic T cells. Type I IFNs are evolutionally conserved cytokines, with broad antimicrobial and immunoregulatory functions. Despite well-characterized roles in spontaneous cancer immunosurveillance, the function of type I IFNs in cancer immunotherapy remains incompletely understood. We utilized genetic mouse models to explore the role of the type I IFN system in CD8+ T-cell immunotherapy. Our results substantiate a complex and plastic phenotypic interconnection between melanoma and myeloid cells in the context of T-cell immunotherapy. Type I IFN signaling in myeloid cells was identified as a key regulator of the balance between antitumor immunity and disease-promoting inflammation, thus supporting the development of novel combinatorial immunotherapies targeting this immune cell compartment. In part 2, we characterized the c-Met inhibitor of the receptor tyrosine kinase c-MET on the efficacy of cancer immunotherapy, which is currently used in the clinic to target oncogenic signaling in tumor cells. We found that concomitant c-MET inhibition promoted adoptive T cell transfer and checkpoint immunotherapies in murine cancer models by increasing effector T cell infiltration in tumors. This therapeutic effect was independent of tumor cell-intrinsic c-MET dependence. Mechanistically, c-MET inhibition impaired the reactive mobilization and recruitment of neutrophils into tumors and draining lymph nodes in response to cytotoxic immunotherapies. In the absence of c-MET inhibition, neutrophils recruited to T cell-inflamed microenvironments rapidly acquired immunosuppressive properties, restraining T cell expansion and effector functions. In cancer patients, high serum levels of the c-MET ligand, HGF, correlated with increased neutrophil counts and poor responses to checkpoint blockade therapies. Our findings reveal a role for the HGF/c-MET pathway in neutrophil recruitment and function and suggest that c-MET inhibitor co-treatment may improve responses to cancer immunotherapy in settings beyond c-MET-dependent tumors. In part 3, we wanted to further develop the HGF-CDK4R24C mouse model to evaluate treatment protocols that combine adoptive T-cell therapies with BRAFV600E signal transduction inhibitors. Here, we reported the unexpected finding that immune cell-poor pigmented and immune cell-rich amelanotic melanomas developed simultaneously in Cdk4R24C-mutant mice upon melanocyte-specific conditional activation of oncogenic BrafV600E and a single application of the carcinogen 7,12-dimethylbenz(a)anthracene. We further showed in a genetic mouse model that constitutively enhanced Hgf-Met signaling cooperates with oncogenic BRAF to drive tumor development and metastatic spread. Activation of oncogenic BRAF in mice with transgenic Hgf overexpression and an oncogenic CDK4 germline mutation accelerated and increased the development of primary cutaneous melanomas. Taken together, our work supports the notion that activated Hgf-Met signaling and oncogenic BRAF can cooperate in melanoma pathogenesis.
Publications
- A Preclinical Model of Malignant Peripheral Nerve Sheath Tumor-like Melanoma Is Characterized by Infiltrating Mast Cells. Cancer Res. 2016 Jan 15;76(2):251-63
Hölzel M, Landsberg J, Glodde N, Bald T, Rogava M, Riesenberg S, Becker A, Jönsson G, Tüting T
(See online at https://doi.org/10.1158/0008-5472.CAN-15-1090) - Reactive Neutrophil Responses Dependent on the Receptor Tyrosine Kinase c-MET Limit Cancer Immunotherapy. Immunity. 2017 Oct 17;47(4):789-802
Glodde N, Bald T, van den Boorn-Konijnenberg D, Nakamura K, O'Donnell JS, Szczepanski S, Brandes M, Eickhoff S, Das I, Shridhar N, Hinze D, Rogava M, van der Sluis TC, Ruotsalainen JJ, Gaffal E, Landsberg J, Ludwig KU, Wilhelm C, Riek-Burchardt M, Müller AJ, Gebhardt C, Scolyer RA, Long GV, Janzen V, Teng MWL, Kastenmüller W, Mazzone M, Smyth MJ, Tüting T, Hölzel M
(See online at https://doi.org/10.1016/j.immuni.2017.09.012) - Activated Hgf-Met Signaling Cooperates with Oncogenic BRAF to Drive Primary Cutaneous Melanomas and Angiotropic Lung Metastases in Mice. J Invest Dermatol. 2020 Jul;140(7):1410-1417
Braun AD, Mengoni M, Bonifatius S, Tüting T, Gaffal E
(See online at https://doi.org/10.1016/j.jid.2019.12.020) - The myeloid cell type I IFN system promotes antitumor immunity over pro-tumoral inflammation in cancer T-cell therapy. Clin Transl Immunology 2021 e1276
Ruotsalainen J, Lopez-Ramos D, Rogava M, Shridhar N, Glodde N, Gaffal E, Hölzel M, Bald T, Tüting T
(See online at https://doi.org/10.1002/cti2.1276)
