CTSS Y132D

We next employed LMP-inducing tool compounds (LLOMe) and clinically used drugs or analogs (desipramine, hexamethylene amiloride) to release cathepsins into the cytosol...The combination of LLOMe-induced LMP and the BCL2 inhibitor venetoclax (VEN) showed increased cytotoxicity in CTSS-hyperactive Karpas422 cells compared to monotherapy and CSTB k/d enhanced this phenotype (Fig A, bottom)...In summary, we show that CSTB is a functionally relevant inhibitor that determines the net activity of LMP-released cytosolic CTSS. Furthermore, LMP-inducing therapies may be a promising approach to sensitize CTSS-hyperactive tumors towards apoptosis by proteolytic cleavage of BCL2 family members.

Clearly, loss of cathepsin S activity delayed lymphoma development and significantly prolonged survival of the mice, indicating that cathepsin S represents an ideal therapeutic target in B cell malignancies.ConclusionOverall, CTSS alterations are key drivers in lymphoma development since it regulates B-cell proliferation and modulation of the interactions with the TME. Further ongoing studies will help us to understand better the mechanistic contribution of CTSS in these processes.

In addition, CTSS hyperactive glioblastoma cell lines U-87 and U-251 also showed MCL-1 dependency following LMP, indicating that cytosolic CTSS hyperactivity primes for MCL-1 dependency across many cancer types. Conclusions Releasing CTSS from the lysosome is novel, attractive concept that can be combined with conventional, apoptosis-inducing therapies.

Loss of CTSS activity reduces lymphoma growth by limiting communication with CD4 T follicular helper cells while inducing antigen diversification and activation of CD8 T cells. Overall, our results suggest that CTSS inhibition has non-redundant therapeutic potential to enhance anti-tumor immune responses in indolent and aggressive lymphomas.

Very similar to previously described, top ten mutated genes were: CREBBP (75%), KMT2D (73%), BCL2 (46%), TNFRSF14 (43%), EZH2 (23%), STAT6 (21%), EP300 (19%), MEF2B (19%), IGLL5 (18%) and ARID1A (17%). Of note, we found that there is one third of FL patients that present with mutations in genes affecting the mTORC1 pathway, showing poor outcomes when treated with R-CVP/R-CHOP but not if treated with R-B. Evaluation of mTORC1 targeted therapies might be of interest in this subset of FL.