Laura Turos-Korgul

Bio: Laura Turos-Korgul is an academic researcher from Nencki Institute of Experimental Biology. The author has contributed to research in topics: Myeloid leukemia & Cytotoxic T cell. The author has an hindex of 1, co-authored 2 publications receiving 5 citations.

Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias.

Abstract: Both chronic myeloid leukemia and acute myeloid leukemia evade the immune response during their development and disease progression. As myeloid leukemia cells modify their bone marrow microenvironment, they lead to dysfunction of cytotoxic cells, such as CD8+ T cells or NK cells, simultaneously promoting development of immunosuppressive regulatory T cells and suppressive myeloid cells. This facilitates disease progression, spreading of leukemic blasts outside the bone marrow niche and therapy resistance. The following review focuses on main immunosuppressive features of myeloid leukemias. Firstly, factors derived directly from leukemic cells - inhibitory receptors, soluble factors and extracellular vesicles, are described. Further, we outline function, properties and origin of main immunosuppressive cells - regulatory T cells, myeloid derived suppressor cells and macrophages. Finally, we analyze interplay between recovery of effector immunity and therapeutic modalities, such as tyrosine kinase inhibitors and chemotherapy.

Targeting Integrated Stress Response by ISRIB combined with imatinib attenuates STAT5 signaling and eradicates therapy-resistant Chronic Myeloid Leukemia cells

Abstract: Integrated Stress Response (ISR) facilitates cellular adaptation to variable environmental conditions by reprogramming cellular response. Activation of ISR was reported in neurological disorders and solid tumours, but its function in hematological malignancies remains largely unknown. Previously we showed that ISR is activated in chronic myeloid leukemia (CML) CD34+ cells, and its activity correlates with disease progression and imatinib resistance. Here we demonstrate that inhibition of ISR by small molecule ISRIB, but not by PERK inhibitor GSK2656157, restores sensitivity to imatinib and eliminates CM Blast Crisis (BC) D34+ resistant cells. We found that in Patient Derived Xenograft (PDX) mouse model bearing CD34+ imatinib/dasatinib-resistant CML blasts with PTPN11 gain-of-function mutation, combination of imatinib and ISRIB decreases leukemia engraftment. Furthermore, genes related to SGK3, RAS/RAF/MAPK, JAK2 and IFNγ pathways were downregulated upon combined treatment. Remarkably, we confirmed that ISRIB and imatinib combination decreases STAT5 phosphorylation and inhibits expression of STAT5-target genes responsible for proliferation, viability and stress response. Thus, our data point to a substantial effect of imatinib and ISRIB combination, that results in transcriptomic deregulation and eradication of imatinib-resistant cells. Our findings suggest such drug combination might improve therapeutic outcome of TKI-resistant leukemia patients exhibiting constitutive STAT5 activation.

PD-1 and TIGIT Are Highly Co-Expressed on CD8+ T Cells in AML Patient Bone Marrow

Abstract: Despite the great success of immune-checkpoint inhibitor (ICI) treatment for multiple cancers, evidence for the clinical use of ICIs in acute myeloid leukemia (AML) remains inadequate. Further exploration of the causes of immune evasion in the bone marrow (BM) environment, the primary leukemia site, and peripheral blood (PB) and understanding how T cells are affected by AML induction chemotherapy or the influence of age may help to select patients who may benefit from ICI treatment. In this study, we comprehensively compared the distribution of PD-1 and TIGIT, two of the most well-studied IC proteins, in PB and BM T cells from AML patients at the stages of initial diagnosis, complete remission (CR), and relapse-refractory (R/R) disease after chemotherapy. Our results show that PD-1 was generally expressed higher in PB and BM T cells from de novo (DN) and R/R patients, while it was partially recovered in CR patients. The expression of TIGIT was increased in the BM of CD8+ T cells from DN and R/R patients, but it did not recover with CR. In addition, according to age correlation analysis, we found that elderly AML patients possess an even higher percentage of PD-1 and TIGIT single-positive CD8+ T cells in PB and BM, which indicate greater impairment of T cell function in elderly patients. In addition, we found that both DN and R/R patients accumulate a higher frequency of PD-1+ and TIGIT+ CD8+ T cells in BM than in corresponding PB, indicating that a more immunosuppressive microenvironment in leukemia BM may promote disease progression. Collectively, our study may help guide the combined use of anti-PD-1 and anti-TIGIT antibodies for treating elderly AML patients and pave the way for the exploration of strategies for reviving the immunosuppressive BM microenvironment to improve the survival of AML patients.

Reduced Absolute Count of Monocytes in Patients Carrying Hematological Neoplasms and SARS-CoV2 Infection

Abstract: Simple Summary In hematological neoplasms associated with COVID-19, immunological dysfunction, including reduced count of non-classical monocytes, has been suggested as a primary driver of morbidity and mortality. In this work, we investigated the contribution of absolute monocyte count to clinical outcome of COVID-19 in 120 patients affected by hematological neoplasms that tested positive to SARS-CoV-2. We found that there was no statistical difference in 30-day mortality, rate of hospitalization for intensive cure and viral clearance at 14 days between fully vaccinated and unvaccinated patients. Increased 30-day mortality was associated with presence of active/progressing disease and absolute monocyte count lower than 400 cells/uL. Reduced absolute counts of monocytes should be used as an alert of increased risk of severe/critical forms of COVID-19 in patients with hematological malignancies, even when the full vaccination cycle has been completed. Abstract Background: Clinical course of COVID-19 depends on several patient-specific risk factors, including immune function, that is largely compromised in cancer patients. Methods: We prospectively evaluated 120 adult consecutive patients (including 34 cases of COVID-19 breakthrough after two full doses of BNT162b2 vaccine) with underlying hematological malignancies and a SARS-CoV-2 infection, in terms of patient’s clinical outcome. Results: Among fully vaccinated patients the achievement of viral clearance by day 14 was more frequent than in unvaccinated patients. Increased 30-day mortality was associated with presence of active/progressing disease and absolute monocyte count lower than 400 cells/uL. Results of multivariable analysis in unvaccinated patients showed that the pre-infection absolute count of monocytes less or equal to 400 cells/mmc, active or progressive disease of the underlying hematological malignancy, the COVID-19 severity identified by hospitalization requirement and lack of viral clearance at 14 days were independent predictors of 1-year overall survival. Conclusions: Taken together, our results indicate that absolute monocyte count determined one month before any documented SARS-CoV-2 infection could identify patients affected by hematological neoplasms with increased risk of inferior overall survival.

Immune Evasion as the Main Challenge for Immunotherapy of Cancer

Abstract: Immune evasion is currently considered one of the most prominent hallmarks of cancer [...].