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2020 ; 84
(ä): 106495
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Blocking drug-induced autophagy with chloroquine in HCT-116 colon cancer cells
enhances DC maturation and T cell responses induced by tumor cell lysate
#MMPMID32298965
Zamame Ramirez JA
; Romagnoli GG
; Falasco BF
; Gorgulho CM
; Sanzochi Fogolin C
; Dos Santos DC
; Junior JPA
; Lotze MT
; Ureshino RP
; Kaneno R
Int Immunopharmacol
2020[Jul]; 84
(ä): 106495
PMID32298965
show ga
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-? 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.