Our strength relies in our multidisciplinary approach and in the combination of state-of-the-art technologies, including single-cell sequencing, high-throughput profiling, and powerful bioinformatic analysis, which have led to ground-breaking discoveries in the medical field. We primarily use patients’ immune and cancer cells in dynamic co-culture models, hoping that the results will be more readily incorporated into clinical patient care.
Moreover, we have several academic and company-sponsored clinical trials ongoing (both phase I and phase II) studying the effects of tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib, bosutinib) in combination with other drugs.
Engaging our own immune system to fight against the cancer has become an increasingly important and promising therapy in many solid tumors, such as melanoma. Disappointingly, the responses to these novel immune activating therapies have been very modest in many blood cancers and limited to only some of the patients. It is not known in detail how blood cancer cells escape the immune cell attack, and which individual mechanisms may account for a patient’s resistance to treatment. We aim to discover more effective immunotherapies, as well as individual resistance and sensitivity mechanisms (personalized medicine).
Chronic myeloid leukemia (CML). During our early years, we widely studied the anti-leukemia immune effects in CML. We discovered that especially the 2nd generation tyrosine kinase inhibitor (TKI) dasatinib has immunomodulatory properties (Kreutzman et al., Blood 2010; Kreutzman et al., Leukemia 2011; Mustjoki et al., Leukemia 2013; Kreutzman et al., Oncoimmunology 2014). Interestingly, the immune-related adverse events of dasatinib have been associated with better treatment responses in advanced CML. Despite the success of TKIs, it is believed that these drugs do not eradicate CML stem cells, and relapses occur often after treatment discontinuation. However, our studies suggest that a proportion of CML patients can discontinue the treatment and that NK cells are important in this successful treatment cessation (Ilander et al., Leukemia 2017).
Accumulation of acquired genetic alterations (somatic mutations) has been considered a hallmark of cancer progression. Mutations occur more frequently during DNA replication, and thus cancers originate more commonly from rapidly proliferating cell types. Recently, we discovered novel somatic mutations in CML and showed how they impact disease prognosis and response both to targeted and immunotherapies (Adnan-Awad et al., Leukemia 2020, Blood Adv 2021, Leukemia 2021, Blood Cancer J 2022).
Finally, we investigated the effects of dasatinib and IFN-α combination treatment in a multicenter clinical trial and discovered that dasatinib drives the T and NK cell immune repertoire toward terminally differentiated phenotypes with dampened functional capabilities, and the addition of IFN-α reverses the phenotypes (Huuhtanen et al., J Clin Invest 2022). Our work supports the combination of IFN-α with tyrosine kinase inhibitor (TKI) therapy, as IFN-α broadens the immune repertoire and restores immunological function.
Other haematological malignancies. Presently, we are also working with other haematological malignancies to characterize their immulonologic landscapes. Together with our collaborators, we analyze gene expression patterns in large-scale genomic data sets and characterize the immune environment in the bone marrow and blood samples with multicolor flow cytometry and multiplexed immunohistochemistry to understand the immune checkpoint molecule expression. The ultimate goal is to identify the patient subsets which may benefit from immune-based therapies, such as immune checkpoint blockade.
After large immunogenomic analysis, we discovered immunological features that are related to different blood cancer subtypes and the survival of patients and described novel cancer-type specific immune checkpoint, epigenetic and genetic alterations (Dufva&Polonen, et al., Cancer Cell 2020). Moreover, we evaluated the immunomodulatory effects of >500 cancer drugs and applied genome wide CRISPR-Cas9 screens to study the sensitivity mechanisms to CAR T (Dufva et al., Blood 2020) and NK cells (Dufva&Gandolfi et al., Immunity 2024) and showed that death receptor signaling is an essential mediator in both cell types.
Solid tumors. In addition to hematological malignancies, our group is also investigating the immune system in solid tumors (Hekim&Ilander et al., Cancer Immunol Res 2017). We analyzed over 10 million T cell receptors (TCRs) from 515 patients with primary or metastatic melanoma and compared it to 783 healthy controls and built an artificial intelligence model for predicting anti-melanoma T cells (Huuhtanen et al., Nat Commun 2022).
Somatic mutations not only occur in cancer patients, but also in hematopoietic stem cells of healthy individuals, and their frequency increases with age. We hypothesize that during normal immune responses when T cells undergo rapid clonal expansion, they may also acquire genetic changes, which may alter their behaviour. In our model disease, large granular lymphocyte (LGL) leukaemia, chronic antigen stimulation is appreciated as a potential initiator for the disease. Interestingly, in LGL leukaemia, somatic mutations in STAT3 gene predispose the patients to autoimmune co-manifestations, such as rheumatoid arthritis (RA) and immune-mediated cytopenias (Koskela HLM&Eldfors S. et al., NEJM 2012; Rajala et al., Hematologica 2014). Therefore, LGL leukemia may be considered as an extreme example of autoimmune response. Recently, we studied the T cell receptor (TCR) repertoire in T-LGLL patients and showed that T-LGLL clonotypes are restricted to individual patients, suggesting that there is not one shared target antigen in T-LGLL (Huuhtanen et al., Nat comm, 2022). However, we also discovered that the majority of leukemic T-LGLL clonotypes share TCR similarities with their non-leukemic repertoire. Thus, an aberrant oligoclonal immune response against a specific antigen can be a disease-inducing and evolution-driving trigger in T-LGLL. The antigen can be both autoantigen or alloantigen, as T-LGLL patients have autoimmune-like symptoms and LGL proliferations have also been observed after viral infections.
Chronic inflammation has been accepted as a potential risk factor for cancer. Our hypothesis is that the pathogenesis of some autoimmune diseases may share similar mechanisms with LGL leukemia. We showed that patients with untreated RA harbour somatic mutations in their clonally expanded cytotoxic lymphocytes (Savola P&Kelkka T et al., Nat Commun 2017). Thus, by using state-or-art technologies, we identified a novel connection between autoimmune inflammation and cancer.
Recently, we showed how somatic mutations influence T cell function and phenotype not only in RA, but also in other auto- and alloimmune diseases including immune mediated bone marrow failure and graft versus host disease (Mustjoki&Young, NEJM 2021; Kim et al., Haematologica 2022; Kim et al., Leukemia 2021; Lundgren et al., Leukemia 2021; Savola et al., Haematologica 2020; Kim et al., Nat Comm 2020).
In collaboration with Pentti Tienari’s lab, we studied somatic mutations in multiple sclerosis (MS). We demonstrated that STAT3 is an outstanding mutational hotspot in CD8+ cells, but the overall mutation prevalence was not increased in CD8+ cells derived from MS patients compared to healthy controls (Valori et al., PLoS One 2022).
In close collaboration with the Institute for Molecular Medicine Finland (FIMM), we apply the cancer cell Drug Sensitivity and Resistance Testing (DSRT) platform to functionally characterize the ex vivo sensitivity to hundreds of compounds in different leukemias both using fresh patient-derived samples as well as using established and experimental cell lines. Our discoveries in T-cell prolymphocytic leukemia (Andersson et al., Leukemia 2017), chronic myeloid leukemia (CML) (Pietarinen et al., Blood Cancer J 2015; Pietarinen et al., Oncotarget 2017) and STAT3-driven lymphocytic malignancies (Kuusanmäki et al., Oncotarget 2017) highlight the importance of the method in disease characterization as well as in the discovery of novel therapy options for different leukemias. We therefore applied high-throughput flow cytometry-based drug profiling to understand the single-cell heterogeneity of drug responses in myeloid leukemias and to develop novel assays to discover immunomodulatory effects of oncology drugs that could synergize with cancer immunotherapies.
We discovered erythroid/megakaryocytic AML to be highly sensitive for BCL-XL inhibition which provides a novel treatment possibility for patients with currently have extremely poor prognosis (Kuusanmäki&Dufva et al., Blood 2023). We also discovered novel pathogenetic mechanisms and targeted therapies for rare aggressive T and NK cell malignancies (Dufva et al., Nat Comm 2018; Huuhtanen et al., Nat Comm 2022; Bhattacharya et al., Blood Cancer J 2022) and some of these discoveries are already now applied in diagnostics.
We have set up a biomarker discovery program, which is performed concurrent to the clinical drug studies, both academic and company sponsored. In the frame of Nordic CML study group we analysed the leukemic stem cell burden at the diagnosis and during TKI therapy and its importance for the therapy response. These analyses have been performed during NordCML006 study, NordCML007 study Enest1st study. In addition to stem cell analysis, we are performing various immunological measurements aiming to understand immunological determinants of successful treatment response. We also headed an immunology biomarker substudy in European wide Euro-Ski study, which evaluated the probability of successful treatment discontinuation in CML.
Moreover, we established significant research collaborations with pharmaceutical companies in which our unit serves as the central immunological biomarker discovery laboratory in international Phase I/II clinical studies.
Recently, we carried out immunological analyses and identified novel biomarkers that correlate to the response to immunotherapies (Huuhtanen J Clin Invest 2022; Hakanen, Cancer Immunol Immunother 2020).