Article ; Online: Blocking drug-induced autophagy with chloroquine in HCT-116 colon cancer cells enhances DC maturation and T cell responses induced by tumor cell lysate.
International immunopharmacology
2020 Volume 84, Page(s) 106495
Abstract: ... the ability of tumor cells to drive DC maturation and enhances the ability of DCs to stimulate T cell ... maturation. DCs sensitized with the lysate of HCT-116 cells previously exposed to such a combination enhanced ... of antineoplastic agents. Exposing tumor cells to low concentrations of select autophagy-inducing antineoplastic agents ...
| Abstract | Autophagy is an important mechanism for tumor escape, allowing tumor cells to recover from the damage induced by chemotherapy, radiation therapy, and immunotherapy and contributing to the development of resistance. The pharmacological inhibition of autophagy contributes to increase the efficacy of antineoplastic agents. Exposing tumor cells to low concentrations of select autophagy-inducing antineoplastic agents increases their immunogenicity and enhances their ability to stimulate dendritic cell (DC) maturation. We tested whether the application of an autophagy-inhibiting agent, chloroquine (CQ), in combination with low concentrations of 5-fluorouracil (5-FU) increases the ability of tumor cells to induce DC maturation. DCs sensitized with the lysate of HCT-116 cells previously exposed to such a combination enhanced the DC maturation/activation ability. These matured DCs also increased the allogeneic responsiveness of both CD4+ and CD8+ T cells, which showed a greater proliferative response than those from DCs sensitized with control lysates. The T cells expanded in such cocultures were CD69+ and PD-1- and produced higher levels of IFN-γ and lower levels of IL-10, consistent with the preferential activation of Th1 cells. Cocultures of autologous DCs and lymphocytes improved the generation of cytotoxic T lymphocytes, as assessed by the expression of CD107a, perforin, and granzyme B. The drug combination increased the expression of genes related to the CEACAM family (BECN1, ATGs, MAPLC3B, ULK1, SQSTM1) and tumor suppressors (PCBP1). Furthermore, the decreased expression of genes related to metastasis and tumor progression (BNIP3, BNIP3L, FOSL2, HES1, LAMB3, LOXL2, NDRG1, P4HA1, PIK3R2) was noted. The combination of 5-FU and CQ increases the ability of tumor cells to drive DC maturation and enhances the ability of DCs to stimulate T cell responses. |
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| MeSH term(s) | Antimetabolites, Antineoplastic/pharmacology ; Autophagy/drug effects ; CD4-Positive T-Lymphocytes/metabolism ; CD8-Positive T-Lymphocytes/metabolism ; Cell Differentiation/drug effects ; Chloroquine/pharmacology ; Dendritic Cells/cytology ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Fluorouracil/pharmacology ; HCT116 Cells ; Humans ; Lymphocyte Activation/drug effects ; Th1 Cells/drug effects ; Th1 Cells/metabolism ; Transcriptional Activation/drug effects | |||||
| Chemical Substances | Antimetabolites, Antineoplastic ; Chloroquine (886U3H6UFF) ; Fluorouracil (U3P01618RT) | |||||
| Keywords | covid19 | |||||
| Language | English | |||||
| Publishing date | 2020-04-13 | |||||
| Publishing country | Netherlands | |||||
| Document type | Journal Article | |||||
| ZDB-ID | 2043785-7 | |||||
| ISSN | 1878-1705 ; 1567-5769 | |||||
| ISSN (online) | 1878-1705 | |||||
| ISSN | 1567-5769 | |||||
| DOI | 10.1016/j.intimp.2020.106495 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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