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Theranostics 2022Prostate cancer is usually considered as immune "cold" tumor with poor immunogenic response and low density of tumor-infiltrating immune cells, highlighting the need to...
Prostate cancer is usually considered as immune "cold" tumor with poor immunogenic response and low density of tumor-infiltrating immune cells, highlighting the need to explore clinically actionable strategies to sensitize prostate cancer to immunotherapy. In this study, we investigated whether docetaxel-based chemohormonal therapy induces immunologic changes and potentiates checkpoint blockade immunotherapy in prostate cancer. We performed transcriptome and histopathology analysis to characterize the changes of prostate cancer immune microenvironment before and after docetaxel-based chemohormonal therapy. Furthermore, we investigated the therapeutic benefits and underlying mechanisms of chemohormonal therapy combined with anti-PD1 blockade using cellular experiments and xenograft prostate cancer models. Finally, we performed a retrospective cohort analysis to evaluate the antitumor efficacy of anti-PD1 blockade alone or in combination with docetaxel-based chemotherapy. Histopathology assessments on patient samples confirmed the enrichment of tumor-infiltrating T cells after chemohormonal therapy. Moreover, we found that docetaxel activated the cGAS/STING pathway in prostate cancer, subsequently induced IFN signaling, resulting in lymphocytes infiltration. In a xenograft mouse model, docetaxel-based chemohormonal therapy prompted the intratumoral infiltration of T cells and upregulated the abundance of PD1 and PD-L1, thereby sensitizing mouse tumors to the anti-PD1 blockade. To determine the clinical significance of these results, we retrospectively analyzed a cohort of 30 metastatic castration-resistant prostate cancer patients and found that docetaxel combined with anti-PD1 blockade resulted in better prostate-specific antigen progression-free survival when compared with anti-PD1 blockade alone. Our study demonstrates that docetaxel activates the antitumoral immune response and facilitates T cell infiltration in a cGAS/STING-dependent manner, providing a combination immunotherapy strategy that would improve the clinical benefits of immunotherapy.
Topics: Animals; Cell Line, Tumor; Disease Models, Animal; Docetaxel; Humans; Immunologic Factors; Immunotherapy; Male; Mice; Nucleotidyltransferases; Prostatic Neoplasms; Retrospective Studies; Tumor Microenvironment
PubMed: 35836810
DOI: 10.7150/thno.73152 -
Journal For Immunotherapy of Cancer May 2022Although the antitumor efficacy of docetaxel (DTX) has long been attributed to the antimitotic activities, its impact on the tumor microenvironment (TME) has recently...
BACKGROUND
Although the antitumor efficacy of docetaxel (DTX) has long been attributed to the antimitotic activities, its impact on the tumor microenvironment (TME) has recently gained more attention. Macrophages are a major component of the TME and play a critical role in DTX efficacy; however, the underlying action mechanisms remain unclear.
METHODS
DTX chemotherapeutic efficacy was demonstrated via both macrophage depletion and C-C motif chemokine ligand 3 (Ccl3)-knockout transgenic allograft mouse model. Ccl3-knockdown and Ccl3-overexpressing breast cancer cell allografts were used for the in vivo study. Combination therapy was used to evaluate the effect of Ccl3 induction on DTX chemosensitivity. Vital regulatory molecules and pathways were identified using RNA sequencing. Macrophage phagocytosis of cancer cells and its influence on cancer cell proliferation under DTX treatment were assessed using an in vitro coculture assay. Serum and tumor samples from patients with breast cancer were used to demonstrate the clinical relevance of our study.
RESULTS
Our study revealed that Ccl3 induced by DTX in macrophages and cancer cells was indispensable for the chemotherapeutic efficacy of DTX. DTX-induced Ccl3 promoted proinflammatory macrophage polarization and subsequently facilitated phagocytosis of breast cancer cells and cancer stem cells. Ccl3 overexpression in cancer cells promoted proinflammatory macrophage polarization to suppress tumor progression and increase DTX chemosensitivity. Mechanistically, DTX induced Ccl3 by relieving the inhibition of cAMP-response element binding protein on Ccl3 via reactive oxygen species accumulation, and Ccl3 then promoted proinflammatory macrophage polarization via activation of the Ccl3-C-C motif chemokine receptor 5-p38/interferon regulatory factor 5 pathway. High CCL3 expression predicted better prognosis, and high CCL3 induction revealed better DTX chemosensitivity in patients with breast cancer. Furthermore, both the Creb inhibitor and recombinant mouse Ccl3 significantly enhanced DTX chemosensitivity.
CONCLUSIONS
Our results indicate that Ccl3 induced by DTX triggers proinflammatory macrophage polarization and subsequently facilitates phagocytosis of cancer cells. Ccl3 induction in combination with DTX may provide a promising therapeutic rationale for increasing DTX chemosensitivity in breast cancer.
Topics: Animals; Breast Neoplasms; Cell Proliferation; Chemokine CCL3; Docetaxel; Female; Humans; Macrophage Activation; Macrophages; Mice; Tumor Microenvironment
PubMed: 35613826
DOI: 10.1136/jitc-2021-003793 -
Journal of Thoracic Oncology : Official... Jan 2023The phase 3 RATIONALE-303 trial (NCT03358875) investigated the efficacy and safety of tislelizumab versus docetaxel in pretreated patients with advanced NSCLC. Here, we... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
The phase 3 RATIONALE-303 trial (NCT03358875) investigated the efficacy and safety of tislelizumab versus docetaxel in pretreated patients with advanced NSCLC. Here, we report the efficacy and safety results and describe the exploratory biomarker analyses.
METHODS
A total of 805 patients aged more than or equal to 18 years with locally advanced or metastatic squamous or nonsquamous NSCLC were randomized 2:1 to intravenous tislelizumab 200 mg or docetaxel 75 mg/m every 3 weeks. Co-primary end points were overall survival (OS) in the intent-to-treat (ITT) and programmed death-ligand 1 (PD-L1) tumor cell expression greater than or equal to 25% populations. The exploratory biomarker analyses included PD-L1 expression, tumor mutation burden, and gene expression profile.
RESULTS
At the prespecified interim analysis (August 10, 2020), the co-primary end point of OS in the ITT population was met, with a statistically significant and clinically meaningful improvement in OS with tislelizumab versus docetaxel (median 17.2 versus 11.9 mo, respectively; hazard ratio [HR] = 0.64, p < 0.0001). At the final analysis (July 15, 2021), the other co-primary end point of OS in the PD-L1 tumor cell greater than or equal to 25% population was further met (median 19.3 versus 11.5 mo, respectively; HR = 0.53, p < 0.0001), and OS continued to improve in the ITT population (median 16.9 versus 11.9 mo, respectively, HR = 0.66). Exploratory biomarker analyses revealed the potential association of NOTCH1-4 mutations with improved tislelizumab efficacy for both OS and progression-free survival, whereas tissue tumor mutation burden correlated with progression-free survival benefit, but not OS benefit. No new safety signals were identified.
CONCLUSIONS
Tislelizumab was found to have a significantly improved and long-term clinical benefit in OS versus docetaxel in pretreated patients with advanced NSCLC, regardless of PD-L1 expression.
Topics: Humans; Docetaxel; B7-H1 Antigen; Lung Neoplasms; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Biomarkers
PubMed: 36184068
DOI: 10.1016/j.jtho.2022.09.217 -
International Immunopharmacology Jun 2023There are several interactions within the tumor microenvironment (TME) that affect the response of cancer cells to therapy. There are also a large number of cells and... (Review)
Review
There are several interactions within the tumor microenvironment (TME) that affect the response of cancer cells to therapy. There are also a large number of cells and secretions in TME that increase resistance to therapy. Following the release of immunosuppressive, pro-angiogenic, and metastatic molecules by certain cells such as tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and cancer cells, immune evasion, angiogenesis, and metastasis may be induced. However, natural killer (NK) cells and cytotoxic CD8 + T lymphocytes (CTLs) can responsively release anticancer molecules. In addition, anticancer drugs can modulate these cells and their interactions in favor of either cancer resistance or therapy. Docetaxel belongs to taxanes, a class of anti-tumor drugs, which acts through the polymerization of tubulin and the induction of cell cycle arrest. Also, it has been revealed that taxanes including docetaxel affect cancer cells and the other cells within TME through some other mechanisms such as modulation of immune system responses, angiogenesis, and metastasis. In this paper, we explain the basic mechanisms of docetaxel interactions with malignant cells. Besides, we review the diverse effects of docetaxel on TME and cancer cells in consequence. Lastly, the modulatory effects of docetaxel alone or in conjunction with other anticancer agents on anti-tumor immunity, cancer cell resistance, angiogenesis, and metastasis will be discussed.
Topics: Humans; Docetaxel; Tumor Microenvironment; Neoplasms; Antineoplastic Agents; T-Lymphocytes, Cytotoxic
PubMed: 37126985
DOI: 10.1016/j.intimp.2023.110214 -
FASEB Journal : Official Publication of... Sep 2023Cuproptosis, a newly discovered programmed cell death induced by copper ions, is associated with the progression and drug resistance of various tumors. Docetaxel plays a...
Cuproptosis, a newly discovered programmed cell death induced by copper ions, is associated with the progression and drug resistance of various tumors. Docetaxel plays a vital role as a first-line chemotherapeutic agent for advanced prostate cancer; however, most patients end up with prostate cancer progression because of inherent or acquired resistance. Herein, we examined the role of cuproptosis in the chemotherapeutic resistance of prostate cancer to docetaxel. We treated prostate cancer cell lines with elesclomol-CuCl , as well as with docetaxel. We performed analyses of CCK8, colony formation tests, cell cycle flow assay, transmission electron microscopy, and mTOR signaling in treated cells, and treated a xenograft prostate cancer model with elesclomol-CuCl and docetaxel in vivo, and performed immunohistochemistry and Western blotting analysis in treated tumors. We found that elesclomol-CuCl could promote cell death and enhance chemosensitivity to docetaxel. Elesclomol-CuCl induced cell death and inhibited the growth of prostate cancer cells relying on copper ions-induced cuproptosis, not elesclomol. In addition, dihydrolipoamide S-acetyltransferase (DLAT) was involved in cuproptosis-enhanced drug sensitivity to docetaxel. Mechanistically, upregulated DLAT by cuproptosis inhibited autophagy, promoted G2/M phase retention of cells, and enhanced the sensitivity to docetaxel chemotherapy in vitro and in vivo via the mTOR signaling pathway. Our findings demonstrated that the cuproptosis-regulated DLAT/mTOR pathway inhibited autophagy and promoted cells in G2/M phase retention, thus enhancing the chemosensitivity to docetaxel. This discovery may provide an effective therapeutic option for treating advanced prostate cancer by inhibiting the chemotherapeutic resistance to docetaxel.
Topics: Male; Humans; Docetaxel; Dihydrolipoyllysine-Residue Acetyltransferase; Copper; Taxoids; Prostatic Neoplasms; TOR Serine-Threonine Kinases; Apoptosis; Autophagy; Cell Line, Tumor
PubMed: 37584654
DOI: 10.1096/fj.202300980R -
Journal of Clinical Rheumatology :... Apr 2020
Topics: Aged; Biopsy; Breast Neoplasms; Docetaxel; Female; Humans; Magnetic Resonance Imaging; Muscles; Myositis; Taxoids
PubMed: 30148754
DOI: 10.1097/RHU.0000000000000888 -
Arteriosclerosis, Thrombosis, and... May 2023The recent identification of the cell-surface protein DSC1 (desmocollin 1) as a negative regulator of HDL (high-density lipoprotein) biogenesis has attracted us to... (Review)
Review
The recent identification of the cell-surface protein DSC1 (desmocollin 1) as a negative regulator of HDL (high-density lipoprotein) biogenesis has attracted us to revisit the old HDL biogenesis hypothesis: HDL biogenesis reduces atherosclerosis. The location and function of DSC1 suggest that DSC1 is a druggable target for the promotion of HDL biogenesis, and the discovery of docetaxel as a potent inhibitor of the DSC1 sequestration of apolipoprotein A-I has provided us with new opportunities to test this hypothesis. The FDA-approved chemotherapy drug docetaxel promotes HDL biogenesis at low-nanomolar concentrations that are far lower than used in chemotherapy. Docetaxel has also been shown to inhibit atherogenic proliferation of vascular smooth muscle cells. In accordance with these atheroprotective effects of docetaxel, animal studies have shown that docetaxel reduces dyslipidemia-induced atherosclerosis. In the absence of HDL-directed therapies for atherosclerosis, DSC1 constitutes an important new target for the promotion of HDL biogenesis, and the DSC1-targeting compound docetaxel serves as a model compound to prove the hypothesis. In this brief review, we discuss opportunities, challenges, and future directions for using docetaxel in the prevention and treatment of atherosclerosis.
Topics: Animals; Lipoproteins, HDL; Docetaxel; Atherosclerosis; Cholesterol, HDL
PubMed: 36861478
DOI: 10.1161/ATVBAHA.122.318275 -
Journal of Thoracic Oncology : Official... May 2019Data on immuno-oncology agents in Chinese patients are limited despite a need for new therapies. We evaluated the efficacy and safety of nivolumab in a predominantly... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Data on immuno-oncology agents in Chinese patients are limited despite a need for new therapies. We evaluated the efficacy and safety of nivolumab in a predominantly Chinese patient population with previously treated NSCLC.
METHODS
CheckMate 078 was a randomized, open-label, phase III clinical trial in patients from China, Russia, and Singapore with squamous or nonsquamous NSCLC that had progressed during/after platinum-based doublet chemotherapy (ClinicalTrials.gov: NCT02613507). Patients with EGFR/ALK alterations were excluded. Patients (N = 504) were randomized 2:1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m every 3 weeks), stratified by performance status, tumor histology, and tumor programmed death ligand 1 expression. The primary endpoint was overall survival (OS); secondary endpoints included objective response rate, progression-free survival, and safety.
RESULTS
OS was significantly improved with nivolumab (n = 338) versus docetaxel (n = 166); median OS (95% confidence interval): 12.0 (10.4-14.0) versus 9.6 (7.6-11.2) months, respectively; hazard ratio (97.7% confidence interval): 0.68 (0.52-0.90); p = 0.0006. Objective response rate was 17% with nivolumab versus 4% with docetaxel; median duration of response was not reached versus 5.3 months. Minimum follow-up was 8.8 months. The frequency of grade 3 or greater treatment-related adverse events was 10% with nivolumab and 48% with docetaxel.
CONCLUSIONS
This is the first phase III study in a predominantly Chinese population reporting results with a programmed death 1 inhibitor. In this population with previously treated advanced NSCLC, nivolumab improved OS versus docetaxel. Results were consistent with global CheckMate 017 and 057 studies.
Topics: Adult; Aged; Antineoplastic Agents, Immunological; Asian People; Carcinoma, Non-Small-Cell Lung; Docetaxel; Female; Humans; Lung Neoplasms; Male; Middle Aged; Nivolumab
PubMed: 30659987
DOI: 10.1016/j.jtho.2019.01.006 -
JAMA Network Open Feb 2023Due to the ongoing bacillus Calmette-Guérin (BCG) shortage, sequential intravesical gemcitabine and docetaxel has been increasingly used as first-line therapy for... (Randomized Controlled Trial)
Randomized Controlled Trial
Comparison of Sequential Intravesical Gemcitabine and Docetaxel vs Bacillus Calmette-Guérin for the Treatment of Patients With High-Risk Non-Muscle-Invasive Bladder Cancer.
IMPORTANCE
Due to the ongoing bacillus Calmette-Guérin (BCG) shortage, sequential intravesical gemcitabine and docetaxel has been increasingly used as first-line therapy for high-risk non-muscle-invasive bladder cancer (NMIBC). However, data directly comparing these 2 therapies are lacking.
OBJECTIVE
To compare the outcomes of patients with high-risk NMIBC treated with gemcitabine and docetaxel vs BCG.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective cohort study was conducted from January 1, 2011, to December 31, 2021. The median (IQR) duration of follow-up was 23 (12-33) months for patients receiving gemcitabine and docetaxel and 49 (27-79) months for patients receiving BCG. All patients were treated at the University of Iowa tertiary care center. A total of 312 patients with high-risk treatment-naive NMIBC were included; 174 patients were treated with BCG therapy and 138 were treated with gemcitabine and docetaxel therapy.
EXPOSURES
After undergoing complete transurethral resection of bladder tumor, patients received either sequential intravesical gemcitabine, 1 g, and docetaxel, 37.5 mg, or 1 vial of BCG. Induction treatments were administered once per week for 6 weeks. Maintenance regimens were initiated if the patient was disease free at the first follow-up visit.
MAIN OUTCOMES AND MEASURES
The primary outcome was high-grade recurrence-free survival (RFS). Survival probabilities were estimated using the Kaplan-Meier method. Cox regression models were used to evaluate the association of covariates with outcomes. Adverse events were reported using the Common Terminology Criteria for Adverse Events, version 5.
RESULTS
Among 312 patients, the median (IQR) age was 73 (66-79) years; 255 patients (81.7%) were male and 292 (93.6%) were White. Baseline clinicopathological characteristics such as sex, smoking status, and pretreatment tumor pathology were similar between treatment groups. High-grade RFS estimates were 76% (95% CI, 69%-82%) at 6 months, 71% (95% CI, 64%-78%) at 12 months, and 69% (95% CI, 62%-76%) at 24 months in the BCG group and 92% (95% CI, 86%-95%) at 6 months, 85% (95% CI, 78%-91%) at 12 months, and 81% (95% CI, 72%-87%) at 24 months in the gemcitabine and docetaxel group. Multivariable Cox regression analyses controlled for age, sex, treatment year, and presence of carcinoma in situ revealed that treatment with gemcitabine and docetaxel was associated with better high-grade RFS (hazard ratio, 0.57; 95% CI, 0.33-0.97; P = .04) and RFS (hazard ratio, 0.56; 95% CI, 0.34-0.92; P = .02) than treatment with BCG. Induction therapy for BCG was associated with greater treatment discontinuation than induction therapy for gemcitabine and docetaxel (9.2% vs 2.9%; P = .02).
CONCLUSIONS AND RELEVANCE
In this cohort study, gemcitabine and docetaxel therapy was associated with less high-grade disease recurrence and treatment discontinuation than BCG therapy. These findings suggest that, while awaiting results from an ongoing randomized clinical trial during the current BCG shortage, use of gemcitabine and docetaxel can be considered for recommendation in updated practice guidelines.
Topics: Humans; Male; Aged; Female; BCG Vaccine; Docetaxel; Gemcitabine; Cohort Studies; Non-Muscle Invasive Bladder Neoplasms; Retrospective Studies
PubMed: 36853609
DOI: 10.1001/jamanetworkopen.2023.0849 -
The Israel Medical Association Journal... Jan 2023
Topics: Humans; Docetaxel; Myositis; Acute Disease
PubMed: 36718745
DOI: No ID Found