Factorial Modeling for Effective Suppression of Directional Noise

Author(s):  
Osamu Ichikawa ◽  
Takashi Fukuda ◽  
Gakuto Kurata ◽  
Steven J. Rennie
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ryan Kolb ◽  
Umasankar De ◽  
Sajid Khan ◽  
Yuewan Luo ◽  
Myung-Chul Kim ◽  
...  

AbstractRegulatory T cells (Tregs) play an important role in maintaining immune homeostasis and, within tumors, their upregulation is common and promotes an immunosuppressive microenvironment. Therapeutic strategies that can eliminate Tregs in the tumor (i.e., therapies that do not run the risk of affecting normal tissues), are urgently needed for the development of cancer immunotherapies. Here we report our discovery of B-cell lymphoma extra-large (BCL-XL) as a potential molecular target of tumor-infiltrating (TI) Tregs. We show that pharmacological degradation of BCL-XL using a newly developed platelet-sparing BCL-XL Proteolysis-targeting chimera (PROTAC) induces the apoptosis of TI-Tregs and the activation of TI-CD8+ T cells. Moreover, these activities result in an effective suppression of syngeneic tumor growth in immunocompetent, but not in immunodeficient or CD8+ T cell-depleted mice. Notably, treatment with BCL-XL PROTAC does not cause detectable damage within several normal tissues or thrombocytopenia. These findings identify BCL-XL as a target in the elimination of TI-Tregs as a component of cancer immunotherapies, and that the BCL-XL-specific PROTAC has the potential to be developed as a therapeutic for cancer immunotherapy.


ACS Omega ◽  
2018 ◽  
Vol 3 (12) ◽  
pp. 16465-16471 ◽  
Author(s):  
Jin Hong Lee ◽  
Jisoo Kang ◽  
Seung-Wan Kim ◽  
Willy Halim ◽  
Margaret W. Frey ◽  
...  

2015 ◽  
Vol 240 (9) ◽  
pp. 1136-1146 ◽  
Author(s):  
Doo Suk Lee ◽  
Binna N. Kim ◽  
Seonung Lim ◽  
Junsub Lee ◽  
Jiyoung Kim ◽  
...  

2016 ◽  
Vol 378 ◽  
pp. 467-472 ◽  
Author(s):  
Yuri Kamon ◽  
Naoko Inoue ◽  
Erika Mihara ◽  
Yukiya Kitayama ◽  
Tooru Ooya ◽  
...  

2017 ◽  
Vol 35 (2) ◽  
pp. e12244 ◽  
Author(s):  
Gerrit Frommeyer ◽  
Magdalena Sterneberg ◽  
Dirk G. Dechering ◽  
Sven Kaese ◽  
Nils Bögeholz ◽  
...  

1976 ◽  
Vol 144 (3) ◽  
pp. 713-725 ◽  
Author(s):  
T Tada ◽  
M Taniguchi ◽  
C S David

The locus of the gene that codes for the antigen-specific suppressive T-cell factor was determined to be in a new subregion "I-J" which locates between I-B and I-C subregions in the H-2 histocompatibility complex. This was shown by two different lines of evidence: (a) The absorbing capacity for the suppressive T-cell factor of several alloantisera against restricted I subregions did not correlate with their specificity for previously known Ia molecules which are coded for by genes in I-A and I-C subregions, but was associated with the specificity for the products of genes putatively present between I-B and I-C subregions. By the occurrence of special recombinant strains, i.e. B10.A(5R), B10.A(3R), B10.S(9R), and B10.HTT, which differ with respect to the I-J subregion, we were able to produce alloantisera which distinguish I-J subregion gene products. The absorption studies using these special alloantisera directed to I-J subregion clearly indicated that the suppressive T-cell factor is a product of I-J subregion gene(s), and that the molecule is distinct from known Ia molecules expressed on splenic B cells. (b) Taking advantage of the fact that there is a strict histocompatibility requirement for the effective suppression between the donor and recipient strains of the suppressive T-cell factor, we were able to determine the required identities of the genes in the H-2 complex existing among those present between I-B and I-C. Again, utilizing the T-cell factors obtained from special recombinant strains, i.e. B10.A(4R) and B10.A(5R), we were able to locate the gene that codes for the suppressive T-cell factor reactive only with relevant haplotype strains between I-B and I-C subregions. These results are most reasonably explained by the presence of a new subregion I-J which is specialized in coding for the suppressive T-cell factor as a different molecule from previously known Ia molecules.


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