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TD-92, a novel erlotinib derivative, depletes tumor-associated macrophages in non-small cell lung cancer via down-regulation of CSF-1R and enhances the anti-tumor effects of anti-PD-1.
- Source :
-
Cancer letters [Cancer Lett] 2021 Feb 01; Vol. 498, pp. 142-151. Date of Electronic Publication: 2020 Nov 21. - Publication Year :
- 2021
-
Abstract
- Recent advances in immune checkpoint inhibition, which augment T-cell immune responses, have highlighted the potential of exploiting one's immune system to combat cancer. However, only a relatively small number of non-small cell lung cancer (NSCLC) patients benefit from immune checkpoint blockade due to the immunosuppressive tumor microenvironment. Therefore, combination immunotherapies are now being developed to achieve maximal therapeutic benefits. In this study, we assessed whether a novel erlotinib derivative, TD-92, which possesses anti-tumor effects across several cancer cell lines, could enhance anti-PD-1 treatment. Our results demonstrated that the combined treatment of anti-PD-1 and TD-92 resulted in a potent anti-tumor response in a Lewis lung carcinoma cancer model, as evidenced by the reduced tumor growth and increased survival. Analysis of immune cell population counts revealed that TD-92 reduced the number of pro-tumorigenic CD11b <superscript>+</superscript> F4/80 <superscript>+</superscript> tumor-associated macrophages, without significantly affecting the total numbers of other major immunocytes. Further experiments showed that TD-92 induced a marked decline in colony stimulating factor 1 receptor (CSF-1R) expression in macrophage cell lines. The results also suggested that c-Cbl-mediated proteasome degradation was involved in TD-92-mediated CSF-1R downregulation. Our data paves the way for the development of additional combination immunotherapies for NSCLC patients.<br /> (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Biomarkers, Tumor metabolism
Carcinoma, Lewis Lung drug therapy
Carcinoma, Lewis Lung metabolism
Carcinoma, Non-Small-Cell Lung metabolism
Cell Line, Tumor
Humans
Immunotherapy methods
Lung Neoplasms metabolism
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Tumor Microenvironment drug effects
Tumor-Associated Macrophages metabolism
Antineoplastic Agents pharmacology
Carcinoma, Non-Small-Cell Lung drug therapy
Down-Regulation drug effects
Erlotinib Hydrochloride pharmacology
Lung Neoplasms drug therapy
Programmed Cell Death 1 Receptor metabolism
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor metabolism
Tumor-Associated Macrophages drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1872-7980
- Volume :
- 498
- Database :
- MEDLINE
- Journal :
- Cancer letters
- Publication Type :
- Academic Journal
- Accession number :
- 33232786
- Full Text :
- https://doi.org/10.1016/j.canlet.2020.10.043