CDK12/13 Inhibition Induces Immunogenic Cell Death and Enhances Anti-PD-1 Anticancer Activity in Breast Cancer

Abstract Background: The T cell response against different tumors is improved by immunogenic cell death (ICD), indicating a role for ICD in augmenting antitumor immunity elicited by the anti-checkpoint antibody anti-programmed death 1 (anti-PD-1). Methods: The effect of SR-4835 on breast cancer was analyzed by cell proliferation and flow cytometry. Calreticulin translocation and HMGB1 and ATP release were detected by flow cytometry, ELISA and luminescence assay, respectively. Immunogenicity in vitro was analyzed by co-culturing of SR-4835 treated cancer cells with bone-marrow derived dendritic cells (BMDCs) and rate of maturation of BMDCs and production of IL-6 in the supernatant were measured. The in vivo antitumor effect was analyzed by syngeneic mouse model followed by flow cytometry for TILs.Results: In the present study, we report a synergistic and durable immune-mediated antitumor response elicited by the combined treatment of SR-4835, a CDK12/13 specific inhibitor, with PD-1 blockade in a murine model of 4T1 breast cancer. The developed combination therapy elicited antitumor activity in immunocompetent mouse tumor models. Furthermore, the SR-4835-treated tumor cells exhibited characteristics of ICD, including the release of high mobility group box 1 (HMGB1) and ATP and the translocation of surface calreticulin (CRT). This activity led to a signiﬁcant T-cell dependent regression of tumors. The enhanced infiltration of T cells and dendritic cell (DC) activation in the tumors of mice treated with both SR-4835 and anti-PD-1 indicate that this combination treatment promotes an improved immune response and suggests a potential mechanism involving anti-PD-1 and SR-4835 activity that enhances anti-PD-1 effects. Conclusion: The results of the present study demonstrate the potential of CDK12/13 inhibition combined with checkpoint inhibition in breast cancer treatment.

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Reprogramming the T cell response to cancer by simultaneous, nanoparticle-mediated PD-L1 inhibition and immunogenic cell death

Journal of Controlled Release ◽

10.1016/j.jconrel.2019.10.047 ◽

2019 ◽

Vol 315 ◽

pp. 126-138 ◽

Cited By ~ 8

Author(s):

Cao Dai Phung ◽

Hanh Thuy Nguyen ◽

Ju Yeon Choi ◽

Thanh Tung Pham ◽

Suman Acharya ◽

...

Keyword(s):

Cell Death ◽

T Cell ◽

Cell Response ◽

T Cell Response ◽

Immunogenic Cell Death

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Abstract B047: Combining natural killer T cell immunotherapy with chemotherapy induced immunogenic cell death to target post-surgical breast cancer metastasis

10.1158/2326-6066.imm2016-b047 ◽

2016 ◽

Author(s):

Simon Gebremeskel ◽

Kaitlyn Tanner ◽

Lynnea Lobert ◽

Brent Johnston

Keyword(s):

Breast Cancer ◽

Cell Death ◽

T Cell ◽

Cancer Metastasis ◽

Breast Cancer Metastasis ◽

Immunogenic Cell Death ◽

Natural Killer T Cell ◽

Cell Immunotherapy ◽

Killer T Cell ◽

T Cell Immunotherapy

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Natural Killer T-cell Immunotherapy in Combination with Chemotherapy-Induced Immunogenic Cell Death Targets Metastatic Breast Cancer

Cancer Immunology Research ◽

10.1158/2326-6066.cir-17-0229 ◽

2017 ◽

Vol 5 (12) ◽

pp. 1086-1097 ◽

Cited By ~ 14

Author(s):

Simon Gebremeskel ◽

Lynnea Lobert ◽

Kaitlyn Tanner ◽

Brynn Walker ◽

Tora Oliphant ◽

...

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Metastatic Breast Cancer ◽

T Cell ◽

Metastatic Breast ◽

Immunogenic Cell Death ◽

Natural Killer T Cell ◽

Cell Immunotherapy ◽

Killer T Cell ◽

T Cell Immunotherapy

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ST09, A Novel Curcumin Derivative, Blocks Cell Migration by Inhibiting Matrix Metalloproteases in Breast Cancer Cells and Inhibits Tumor Progression in EAC Mouse Tumor Models

Molecules ◽

10.3390/molecules25194499 ◽

2020 ◽

Vol 25 (19) ◽

pp. 4499

Author(s):

Snehal Nirgude ◽

Raghunandan Mahadeva ◽

Jinsha Koroth ◽

Sujeet Kumar ◽

Kothanahally S. Sharath Kumar ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Flow Cytometry ◽

Cell Death ◽

Cell Migration ◽

Drug Toxicity ◽

Mouse Tumor ◽

Curcumin Derivative

Purpose: Curcumin is known for its anticancer and migrastatic activity in various cancers, including breast cancer. Newer curcumin derivatives are being explored to overcome limitations of curcumin like low bioavailability, stability, and side effects due to its higher dose. In this study, the synthesis of ST09, a novel curcumin derivative, and its antiproliferative, cytotoxic, and migrastatic properties have been explored both in vitro and in vivo. Methods: After ST09 synthesis, anticancer activity was studied by performing standard cytotoxicity assays namely, lactate dehydrogenase (LDH) release assay, 3-(4, 5-dimethylthiazol-2-yl)-2–5-diphenyletrazolium bromide (MTT), and trypan blue exclusion assay. Annexin-FITC, cell cycle analysis using flow cytometry, and Western blotting were performed to elucidate cell death mechanisms. The effect on the inhibition of cell migration was studied by transwell migration assay. An EAC (Ehrlich Ascites carcinoma) induced mouse tumor model was used to study the effect of ST09 on tumor regression. Drug toxicity was measured using aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), and flow-cytometry based lymphocyte count. Histological analysis was performed for assessment of any tissue injury post ST09 treatment. Results: ST09 shows an approximate 100-fold higher potency than curcumin, its parent compound, on breast tumor cell lines MCF-7 and MDA-MB231. ST09 arrests the cell cycle in a cell type-specific manner and induces an intrinsic apoptotic pathway both in vitro and in vivo. ST09 inhibits migration by downregulating matrix metalloprotease 1,2 (MMP1,2) and Vimentin. In vivo, ST09 administration led to decreased tumor volume in a mouse allograft model by boosting immunity with no significant drug toxicity. Conclusion: ST09 exhibits antiproliferative and cytotoxic activity at nanomolar concentrations. It induces cell death by activation of the intrinsic pathway of apoptosis both in vitro and in vivo. It also inhibits migration and invasion. This study provides evidence that ST09 can potentially be developed as a novel antitumor drug candidate for highly metastatic and aggressive breast cancer.

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Oleandrin Induces Immunogenic Cell Death Via the PERK/elF2α/ATF4/CHOP Pathway in Breast Cancer

10.21203/rs.3.rs-135608/v1 ◽

2020 ◽

Author(s):

Xiaoxi Li ◽

Jian Zheng ◽

Shi Chen ◽

Fan-dong Meng ◽

Jing Ning ◽

...

Keyword(s):

Breast Cancer ◽

Flow Cytometry ◽

Cell Death ◽

Er Stress ◽

Cancer Cells ◽

Western Blotting ◽

Breast Cancer Cells ◽

Immunogenic Cell Death ◽

Activation Markers ◽

Qrt Pcr

Abstract Background Chemotherapeutic agents have been linked to immunogenic cell death (ICD) induction that is capable of augmenting antitumor immune surveillance. The cardiac glycoside oleandrin, which inhibits Na+/K+-ATPase pump (NKP), has been shown to suppress breast cancer growth via inducing apoptosis. However, the implications of oleandrin in antitumor immune response and potential ICD induction remain unexplored till now, which is investigated in the present study.Methods Calreticulin (CRT) exposure was detected by immunofluorescence and flow cytometry, and high mobility group protein B1 (HMGB1) and Adenosine Triphosphate (ATP) secretion was quantified by ELISA and both the intracellular and extracellular expression of Heat shock protein 70/90 (HSP70/90) was detected by western blotting in breast cancer cells treated with oleandrin. Dendritic cells (DCs) were co-cultured with oleandrin-treated breast cancer cells before the expressions of activation markers and cytokines were examined by quantitative real time polymerase chain reaction (qRT-PCR), ELISA, and flow cytometry. Immune activation effects of oleandrin were determined in murine breast cancer model using BALB/C mice. The differential mRNA expression incurred by oleandrin was investigated by mRNA sequencing and subsequently confirmed by qRT-PCR and Western blotting. Results Oleandrin treatment induced CRT exposure on cell surface and the release of HMGB1, HSP70/90 and ATP. The maturation and activation of DCs were increased by co-culturing with oleandrin-treated cancer cells, which subsequently enhanced CD8+ T cell cytotoxicity. In animal models, oleandrin inhibited tumor growth and increased tumor infiltrating lymphocytes including DCs and T cells. Mechanistically, oleandrin induced endoplasmic reticulum (ER) stress associated caspase independent immunogenic cell death (ICD) mainly through PERK/elF2α/ATF4/CHOP pathway. Activation of IRE1 pathway but not ATF6, the other two canonical sensors of ER stress, was also observed. Conclusion Oleandrin triggered ER stress and induced ICD-mediated immune destruction of breast cancer cells. Oleandrin combined with immune checkpoint inhibitors might improve the efficacy of immunotherapy.

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Laser nanobubbles induce immunogenic cell death in breast cancer

Nanoscale ◽

10.1039/d0nr06587k ◽

2021 ◽

Vol 13 (6) ◽

pp. 3644-3653

Author(s):

Hieu T. M. Nguyen ◽

Nitesh Katta ◽

Jessica A. Widman ◽

Eri Takematsu ◽

Xu Feng ◽

...

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Dendritic Cell ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Cell Activation ◽

Immunogenic Cell Death ◽

Dendritic Cell Activation

Laser nanobubbles induce dendritic cell activation in breast cancer cells.

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Oncolytic Virotherapy Treatment of Breast Cancer: Barriers and Recent Advances

Viruses ◽

10.3390/v13061128 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1128

Author(s):

Amy Kwan ◽

Natalie Winder ◽

Munitta Muthana

Keyword(s):

Breast Cancer ◽

Clinical Trials ◽

Cell Death ◽

Immune System ◽

Menopausal Status ◽

Oncolytic Virotherapy ◽

Immunogenic Cell Death ◽

Tumour Type ◽

Common Cancer ◽

Direct Cell

Oncolytic virotherapy (OV) is an emerging class of immunotherapeutic drugs. Their mechanism of action is two-fold: direct cell lysis and unmasking of the cancer through immunogenic cell death, which allows the immune system to recognize and eradicate tumours. Breast cancer is the most common cancer in women and is challenging to treat with immunotherapy modalities because it is classically an immunogenically “cold” tumour type. This provides an attractive niche for OV, given viruses have been shown to turn “cold” tumours “hot,” thereby opening a plethora of treatment opportunities. There has been a number of pre-clinical attempts to explore the use of OV in breast cancer; however, these have not led to any meaningful clinical trials. This review considers both the potential and the barriers to OV in breast cancer, namely, the limitations of monotherapy and the scope for combination therapy, improving viral delivery and challenges specific to the breast cancer population (e.g., tumour subtype, menopausal status, age).

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