Research group - Dhifaf Sarhan
Our mission is to develop novel immunotherapies for cancer. Our research focuses on understanding the mechanisms that contribute to an immune suppressive tumor microenvironment (TME) in treatment resistant cancers biased by sex dimorphism and utilizing targeted therapies to reshape the immune regulatory TME and to equip Natural killer cells (NK cells) with immune memory features against solid tumors.
Immunotherapy for cancer has revolutionized the clinical practice, however, it is inefficient in more than 60% of all cancers due to highly immune-suppressive tumor microenvironment (TME) orchestrated by immune suppressor cells, which limit the infiltration of tumor-targeting immune cells, alternatively inhibit antigen-presentation and cytotoxic cell anti-tumor activity in situ resulting in ineffective immunotherapies. Here is a brief introduction to main projects of our group:
Project I: Adaptive NK cell immunological memory in solid tumors
For decades NK cells were believed to lack the immunological memory, however recent groundbreaking research by us and others revealed the opposite. We discovered novel mechanisms used by a subset of NK cells with immunological memory, called adaptive NK cells, to resist the suppressive tumor environment. In this project we focus on investigating the molecular mechanisms behind NK cell memory to tumors and the crosstalk with antigen presenting cells like dendritic cells and B cells in cancer.
Project II: Antibody targeting of suppressive myeloid cells for cancer immunotherapy
The goal for this project is to identify specific targets for tumor-associated macrophages and myeloid-derived suppressor cells to reprogram their suppressive nature and later develop target antibodies to relieve the anti-tumor activity of NK cells and T cells. Currently we are studying G-coupled protein receptors as therapeutic targets in GI-tract cancers.
Project III: Study the mechanisms of immune exclusion in advanced tumors highly infiltrated by myeloid cells
In this project, we study the myeloid cell-dependent inhibitory mechanisms of NK and T cell infiltration into cold and immune excluded pancreas tumors. Patient tumor and blood specimens are provided by national and international collaborators. Further, we are extensively examining the receptor signal integration in suppressive myeloid cells.
Project IV: Studies of sexual immune dimorphism in the TME
We found that a g-coupled protein receptor has predictive value for female cancer patients. Hormone regulation of this receptor function has been shown to induce anti-inflammatory properties in macrophages. This receptor impacts the immune landscape in TME biased by gender dimorphism. Extensive examination of the signal integration is needed to further elucidate its mechanism of action and clinical impact.
Research Group Leader Dhifaf Sarhan
Ahmed Husseini, Mariana Alcocer Bonifaz, Catarina Pelicano, Martin Borgmann, Suborna Mastafa, Caroline Driescher
Cell culture of healthy and tumor material, Flow cytometry, advanced/live microscopy, immune assays, 3D tumor models.
The Swedish Cancer Society, Sjöberg foundation, KI foundations, Sigurd och Elsa Goljes Minne, KID KI-doctoral support.
Study programme in medicine, Biomedical science programme, doctoral education.
Targeting MARCO and IL-37R on immunosuppressive macrophages in lung cancer blocks regulatory T cells and supports cytotoxic lymphocyte function.
La Fleur L, Botling J, He F, Pelicano C, Zhou C, He C, Palano G, Mezheyeuski A, Micke P, Ravetch JV, Karlsson MCI, Sarhan D
Cancer Res 2020 Dec;():
Targeting a scavenger receptor on tumor-associated macrophages activates tumor cell killing by natural killer cells.
Eisinger S, Sarhan D, Boura VF, Ibarlucea-Benitez I, Tyystjärvi S, Oliynyk G, Arsenian-Henriksson M, Lane D, Wikström SL, Kiessling R, Virgilio T, Gonzalez SF, Kaczynska D, Kanatani S, Daskalaki E, Wheelock CE, Sedimbi S, Chambers BJ, Ravetch JV, Karlsson MCI
Proc Natl Acad Sci U S A 2020 12;117(50):32005-32016
Mesenchymal stromal cells shape the MDS microenvironment by inducing suppressive monocytes that dampen NK cell function.
Sarhan D, Wang J, Sunil Arvindam U, Hallstrom C, Verneris MR, Grzywacz B, Warlick E, Blazar BR, Miller JS
JCI Insight 2020 03;5(5):
161533 TriKE stimulates NK-cell function to overcome myeloid-derived suppressor cells in MDS.
Sarhan D, Brandt L, Felices M, Guldevall K, Lenvik T, Hinderlie P, Curtsinger J, Warlick E, Spellman SR, Blazar BR, Weisdorf DJ, Cooley S, Vallera DA, Önfelt B, Miller JS
Blood Adv 2018 06;2(12):1459-1469
Adaptive NK Cells Resist Regulatory T-cell Suppression Driven by IL37.
Sarhan D, Hippen KL, Lemire A, Hying S, Luo X, Lenvik T, Curtsinger J, Davis Z, Zhang B, Cooley S, Cichocki F, Blazar BR, Miller JS
Cancer Immunol Res 2018 07;6(7):766-775