A novel copper chelate modulates tumor associated macrophages to promote anti-tumor response of T cells.
BACKGROUND
At the early stages of carcinogenesis, the induction of tumor specific T cell mediated immunity seems to block the tumor growth and give protective anti-tumor immune response. However, tumor associated macrophages (TAMs) might play an immunosuppressive role and subvert this anti tumor immunity leading to tumor progression and metastasis.


RESULTS
The Cu (II) complex, (chelate), copper N-(2-hydroxy acetophenone) glycinate (CuNG), synthesized by us, has previously been shown to have a potential usefulness in immunotherapy of multiple drug resistant cancers. The current study demonstrates that CuNG treatment of TAMs modulates their status from immunosuppressive to proimmunogenic nature. Interestingly, these activated TAMs produced high levels of IL-12 along with low levels of IL-10 that not only allowed strong Th1 response marked by generation of high levels of IFN-gamma but also reduced activation induced T cell death. Similarly, CuNG treatment of peripheral blood monocytes from chemotherapy and/or radiotherapy refractory cancer patients also modulated their cytokine status. Most intriguingly, CuNG treated TAMs could influence reprogramming of TGF-beta producing CD4(+)CD25(+) T cells toward IFN-gamma producing T cells.


CONCLUSIONS
Our results show the potential usefulness of CuNG in immunotherapy of drug-resistant cancers through reprogramming of TAMs that in turn reprogram the T cells and reeducate the T helper function to elicit proper anti-tumorogenic Th1 response leading to effective reduction in tumor growth.
Chatterjee
Shilpak
S
Department of In Vitro Carcinogenesis and Cellular Chemotherapy, Chittaranjan National Cancer Institute, Kolkata, India.
Mookerjee
Ananda
A
Basu
Jayati Mookerjee
JM
Chakraborty
Paramita
P
Ganguly
Avishek
A
Adhikary
Arghya
A
Mukhopadhyay
Debanjan
D
Ganguly
Sudipto
S
Ganguli
Sudipta
S
Banerjee
Rajdeep
R
Ashraf
Mohammad
M
Biswas
Jaydip
J
Das
Pradeep K
PK
Sa
Gourisankar
G
Chatterjee
Mitali
M
Das
Tanya
T
Choudhuri
Soumitra Kumar
SK
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002614:Chelating Agents / Q000494:pharmacology*; D003300:Copper / Q000737:chemistry* / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007107:Immune System; D007167:Immunotherapy / Q000379:methods; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D009362:Neoplasm Metastasis; D009942:Organometallic Compounds / Q000494:pharmacology*; D018417:Th1 Cells
D002614:Chelating Agents; D053645:Interleukin-2 Receptor alpha Subunit; D009942:Organometallic Compounds; C515714:copper (N-2-hydroxyacetophenone)glycinate; D016753:Interleukin-10; D018664:Interleukin-12; D003300:Copper; D005998:Glycine