Přednáška Dr. Tanmoye Sahy

Ve dnech 1.-3.11. bude na naší fakultě probíhat návštěva Dr. Tanmoye Sahy z Harvard Medical School a Brigham and Women´s Hospital z Bostonu. V rámci této bude mít dvě přednášky, jednu obecnou pro univerzitu v rámci Life Science Series Seminars a druhou tématicky více metodicky zaměřenou na Ústavu patologické fyziologie LF MU. Tato proběhne 3.11. v seminární místnosti 124 v přízemí pavilonu A18

Cancer cells as immune vampires

Cancer progresses by evading the immune system. The current understanding of immune evasion primarily relies on the ability of the cancer cells to express ligands that engage immune checkpoints and release inhibitory cytokines and exosomes for modulating the immune system. For example, cancer cells express ‘self’ Program death ligand-1 (PDL1), which binds to immune checkpoints PD1 on T cells, leading to immune suppression. Blocking these ligand-immune checkpoint interactions can exert long-lasting clinical benefits, but only a fraction of cancer patients respond to such immunotherapies. Cancer cells deploy multiple immune evasion strategies, thereby introducing redundancies or adaptive resistance mechanisms that limit the effectiveness of immune checkpoint inhibitors (ICIs).

Recently, we found a unique mechanism of immune evasion technique by cancer cells hijacking mitochondria from immune cells via nanoscale communications. Using field emission scanning electron microscopy (FESEM), and fluorophore-tagged mitochondrial transfer tracing, we demonstrate that the mitochondria transfer happens from immune cells to cancer cells via nanoscale communication. Mitochondria, the powerhouse of the cell, are essential for metabolism, survival, and activation of immune cells, such as T cells. The transfer of mitochondria cells metabolically empowers the cancer cells and depletes T cells. As a result of metabolic depletion of the T cell, the traditional immunotherapy by immune checkpoint becomes insignificant.

Inhibition of the nanotube-mediated mitochondria transfer from T cells to cancer cells holds tremendous potential to block the unique immune evasion by cancer cells. The nanoscale connections are mainly composed of actin cytoskeletal elements and serve as a path for mitochondrial movement from immune cell to cancer cell. Although numerous extracellular and intracellular signals can affect actin cytoskeletal remodeling, most of these signals converge on a group of small GTPases-exocyst complexes. Knockdown of exocyst proteins, either Sec3 or Sec5, by siRNA-mediated transfection resulted in the reduction of mitochondria transport compared to control. We performed molecular dynamic simulations to identify the potential inhibitors for the exocyst proteins. We have identified a drug candidate, TS-1, which successfully inhibits the mitochondria transfer from the immune cell to the cancer cell. We have used a bioengineering approach to load TS-1 in liposomal nanotherapeutics for selective tumor delivery. The TS-1-Nano showed significant inhibition of tumor growth in syngeneic mouse tumor models. We observed a considerable increase in the intertumoral T-cell population with treatment. Furthermore, the use of TS-1 in combination with an anti-PD1 inhibitor resulted in effective tumor reduction in the 4T1 model, which typically responds poorly to anti-PD1 therapy alone. The use of such inhibitors, along with traditional ICIs, can be the potential next-generation therapeutic strategy.

Reference:

Saha, T., Dash, C., Jayabalan, R. et al. Intercellular nanotubes mediate mitochondrial trafficking between cancer and immune cells. Nat. Nanotechnol. 17, 98–106 (2022). https://doi.org/10.1038/s41565-021-01000-4