Research Group Dr. Mélanie Tichet

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

investigate susceptibility and resistance to immunotherapies (innate and acquired),
elucidate cancer immunosuppressive barriers and the means to transform them into components that elicit tumor immunity,
and
dissect T cell activity and dysfunction.

Team

Selected Publications

Tichet, M., Wullschleger, S., Chryplewicz, A., Fournier, N., Marcone, R., Kauzlaric, A., Homicsko, K., Deak, L.C., Umaña, P., Klein, C., et al. (2023).
Bispecific PD1-IL2v and anti-PD-L1 break tumor immunity resistance by enhancing stem-like tumor-reactive CD8+ T cells and reprogramming macrophages.
Immunity 56, 162-179.e6. 10.1016/j.immuni.2022.12.006.
• Highlighted by: Immunity, Jan 2023 : 10.1016/j.immuni.2022.12.012

Zeng, Q., Saghafinia, S., Chryplewicz, A., Fournier, N., Christe, L., Xie, Y.-Q., Guillot, J., Yucel, S., Li, P., Galván, J.A., (…), Tichet, M., Homicsko, K., Hanahan, D. (2022).
Aberrant hyperexpression of the RNA binding protein FMRP in tumors mediates immune evasion.
Science 378, eabl7207.10.1126/science.abl7207.

Chryplewicz, A., Scotton, J., Tichet, M., Zomer, A., Shchors, K., Joyce, J.A., Homicsko, K., and Hanahan, D. (2022).
Cancer cell autophagy, reprogrammed macrophages, and remodeled vasculature in glioblastoma triggers tumor immunity.
Cancer Cell 40, 1111-1127.e9.10.1016/j.ccell.2022.08.014.

Codarri Deak, L., Nicolini, V., Hashimoto, M., Karagianni, M., Schwalie, P.C., Lauener, L., Varypataki, E.M., Richard, M., Bommer, E., Sam, J., (…),Tichet, M., Hanahan D., (...), et al. (2022).
PD-1-cis IL-2R agonism yields better effectors from stem-like CD8+ T cells.
Nature 610, 161–172.10.1038/s41586-022-05192-0.

More Publications

Latifa Bakiri
Mélanie Tichet
Carolina Marques
Martin K Thomsen
Elizabeth A Allen
Stefanie Stolzlechner
Ke Cheng
Kazuhiko Matsuoka
Massimo Squatrito
Douglas Hanahan
Erwin F Wagner

A new effLuc/Kate dual reporter allele for tumor imaging in mice

Dis Model Mech. 2025 Jan 1;18(1):DMM052130. doi: 10.1242/dmm.052130. Epub 2025 Jan 31.

ABSTRACT

Genetically engineered mouse models (GEMMs) are instrumental for…

Research Group Dr. Mélanie Tichet

Immunoregulatory mechanisms in the tumor microenvironment and resistance to therapy

Young Soo Hwang

Rian Mc Neill

Dr. Mélanie Tichet

Maresa Weitmann

A new effLuc/Kate dual reporter allele for tumor imaging in mice

Bispecific PD1-IL2v and anti-PD-L1 break tumor immunity resistance by enhancing stem-like tumor-reactive CD8+ T cells and reprogramming macrophages

Aberrant hyperexpression of the RNA binding protein FMRP in tumors mediates immune evasion

PD-1-cis IL-2R agonism yields better effectors from stem-like CD8+ T cells

Cancer cell autophagy, reprogrammed macrophages, and remodeled vasculature in glioblastoma triggers tumor immunity

Myeloid Cells Orchestrate Systemic Immunosuppression, Impairing the Efficacy of Immunotherapy against HPV+ Cancers

ALK7 Signaling Manifests a Homeostatic Tissue Barrier That Is Abrogated during Tumorigenesis and Metastasis

Nanoparticle Conjugation of Human Papillomavirus 16 E7-long Peptides Enhances Therapeutic Vaccine Efficacy against Solid Tumors in Mice

Targeting the Proteasome-Associated Deubiquitinating Enzyme USP14 Impairs Melanoma Cell Survival and Overcomes Resistance to MAPK-Targeting Therapies

SIGMAR1 Regulates Membrane Electrical Activity in Response to Extracellular Matrix Stimulation to Drive Cancer Cell Invasiveness

Tumour-derived SPARC drives vascular permeability and extravasation through endothelial VCAM1 signalling to promote metastasis

Risk for nevus transformation and melanoma proliferation and invasion during natalizumab treatment: four years of dermoscopic follow-up with immunohistological studies and proliferation and invasion assays

Metformin blocks melanoma invasion and metastasis development in AMPK/p53-dependent manner

The epithelial-mesenchymal transition (EMT) regulatory factor SLUG (SNAI2) is a downstream target of SPARC and AKT in promoting melanoma cell invasion

Imatinib triggers mesenchymal-like conversion of CML cells associated with increased aggressiveness

The p53/p21Cip1/ Waf1 pathway mediates the effects of SPARC on melanoma cell cycle progression

Regulation of HLA class I surface expression requires CD99 and p230/golgin-245 interaction

Bispecific PD1-IL2v and anti-PD-L1 break tumor immunity resistance by enhancing stem-like tumor-reactive CD8⁺ T cells and reprogramming macrophages

PD-1-cis IL-2R agonism yields better effectors from stem-like CD8⁺ T cells

Myeloid Cells Orchestrate Systemic Immunosuppression, Impairing the Efficacy of Immunotherapy against HPV⁺ Cancers