CAR-T Cells Surface-Engineered with Drug-Encapsulated Nanoparticles Can Ameliorate Intratumoral T-cell Hypofunction

Siriwon, Natnaree; Kim, Yu Jeong; Siegler, Elizabeth L.; Chen, Xianhui; Rohrs, Jennifer A.; Liu, Yarong; Wang, Pin

doi:10.1158/2326-6066.cir-17-0502

Cited by 122 publications

(83 citation statements)

References 49 publications

(76 reference statements)

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“…Targeting components of adenosinergic pathway including ectonucleotidases (CD73, CD39) and adenosine receptors has been investigated in cancer-immunotherapy [14][15][16]. Blocking the effects of adenosine on T cells has been achieved by pharmacological agents, antibodies and molecular methods [17][18][19][20][21][22]. In the current study, the effects of A2aR gene knockdown and pharmacologic inhibition on MSLN-specific CAR T cells were investigated.…”

Section: Discussionmentioning

confidence: 99%

Genetic and pharmacological targeting of A2a receptor improves function of anti-mesothelin CAR T cells

Masoumi

Jafarzadeh

Mirzaei

et al. 2020

J Exp Clin Cancer Res

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Background: CAR T cell-based therapies have shown promising results in hematological malignancies. Results of CAR T cell projects in solid tumors have been less impressive, and factors including lack of targetable antigens and immunosuppressive tumor microenvironment (TME) have been suggested as culprits. Adenosine, a metabolite which is highly produced in TME, is known to mediate the suppression of anti-tumor T cell responses via binding and signaling through adenosine 2a receptor (A2aR). Methods: In this study, the expression of A2aR and the effects of its activation on the function of fully human anti-mesothelin CAR T cells (MSLN-CAR T), were analyzed. Afterwards, the molecular and pharmacological means to overcome the inhibitory effects of A2aR signaling on CAR T cell function were used. This was performed by targeting A2aR expression in MSLN-CAR T cells using various anti-A2aR shRNA sequences embedded in the CAR vector and an A2aR pharmacological antagonist, SCH-58261. Statistical analyses were performed Prism 7 software. Results: Our experiments showed significant A2aR upregulation on T cells during the CAR T cell production procedure (cell activation and transduction). Activation of adenosine signaling using adenosine analog led to the suppression of all major anti-tumor functions in MSLN-CAR T cells. Interestingly, CAR T cells that carried the anti-A2aR shRNA sequences were resistant to the inhibitory effects of adenosine signaling. Pharmacological inhibition of A2aR reversed the reduction in CAR T cell proliferation and cytokine response caused by the adenosine analog; however, it failed to rescue the cytotoxic function of the cells. Conclusion: Altogether, our results indicate that mitigating A2aR signaling by genetic targeting of the receptor might be a promising approach in improving CAR T cell function in an unreceptive microenvironment and could potentially improve the outcome of treatment in clinical settings.

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Section: Discussionmentioning

confidence: 99%

Genetic and pharmacological targeting of A2a receptor improves function of anti-mesothelin CAR T cells

Masoumi

Jafarzadeh

Mirzaei

et al. 2020

J Exp Clin Cancer Res

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“…A hypoxic TME facilitates IL-6 release from CSCs by increasing the rate of expression for adenosine within the TME (Lan et al, 2018). Adenosine has been identified as a potent proinvasive factor (Siriwon et al, 2018), and it is a strong stimulator of Treg immunosuppressive activity (Ghalamfarsa et al, 2018) and a suppressor of CTLs (Y. . Cross-talking between CSCs with other cells within TME has been shown in proliferative rates and are not responsible for long-term tumor growth (Batlle & Clevers, 2017;Hermann & Sainz, 2018).…”

Section: Endothelial Cellsmentioning

confidence: 99%

Cancer stem cells (CSCs) in cancer progression and therapy

Najafi

Farhood

Mortezaee

2018

Journal Cellular Physiology

429

268

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Cancer stem cells (CSCs) are self‐renewable cell types that are identified in most types of liquid and solid cancers and contributed to tumor onset, expansion, resistance, recurrence, and metastasis after therapy. CSCs are identified from the expression of cell surface markers, which is tumor‐type dependent. The transition between CSCs with cancer cells and other non‐CSCs occurs in cancers, which is possibly under the control of signals from CSCs and tumor microenvironment (TME), including CSC niche. Cancer‐associated fibroblasts are among the most influential cells for promoting both differentiation of CSCs and dedifferentiation of non‐CSCs toward attaining a CSC‐like phenotype. WNT/β‐catenin, transforming growth factor‐β, Hedgehog, and Notch are important signals for maintaining self‐renewal in CSCs. An effective therapeutic strategy relies on targeting both CSCs and non‐CSCs to remove a possible chance of tumor relapse. There are multiple ways to target CSCs, including immunotherapy, hormone therapy, (mi)siRNA delivery, and gene knockout. Such approaches can be designed for suppressing CSC stemness, tumorigenic cues from TME, CSC extrinsic and/or intrinsic signaling, hypoxia or for promoting differentiation in the cells. Because of sharing a range of characteristics to normal stem/progenitor cells, CSCs must be targeted based on their unique markers and their preferential expression of antigens.

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“…Adenosine is a known proinvasive factor secreted by cancer cells (Y. Liu, Geng, et al, 2018) in response to tissue damage and cellular stressors (Siriwon et al, 2018). Adenosine stimulates Tregs for strengthening their immunosuppressive functions (Ghalamfarsa et al, 2018) and suppressing the activity of CTLs.…”

Section: Cancer Cellsmentioning

confidence: 99%

Contribution of regulatory T cells to cancer: A review

Najafi

Farhood

Mortezaee

2018

Journal Cellular Physiology

155

103

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Regulatory T cells (Tregs) represent a low number of T‐cell population under normal conditions, and they play key roles for maintaining immune system in homeostasis. The number of these cells is extensively increased in nearly all cancers, which is for dampening responses from immune system against cancer cells, metastasis, tumor recurrence, and treatment resistance. The interesting point is that apoptotic Tregs are stronger than their live counterparts for suppressing responses from immune system. Tregs within the tumor microenvironment have extensive positive cross‐talks with other immunosuppressive cells including cancer‐associated fibroblasts, cancer cells, macrophage type 2 cells, and myeloid‐derived suppressor cells, and they have negative interactions with immunostimulatory cells including cytotoxic T lymphocytes (CTL) and natural killer cells. A wide variety of markers are expressed in Tregs, among them forkhead box P3 (FOXP3) is the most specific marker and the master regulator of these cells. Multiple signals are activated by Tregs including transforming growth factor‐β, signal transducer and activator of transcription, and mTORC1. Treg reprogramming from an immunosuppressive to immunostimulatory proinflammatory phenotype is critical for increasing the efficacy of immunotherapy. This would be applicable through selective suppression of tumor‐bearing receptors in Tregs, including FOXP3, programmed death‐1, T‐cell immunoglobulin mucin‐3, and CTL‐associated antigen‐4, among others. Intratumoral Tregs can also be targeted by increasing the ratio for CTL/Treg.

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CAR-T Cells Surface-Engineered with Drug-Encapsulated Nanoparticles Can Ameliorate Intratumoral T-cell Hypofunction

Cited by 122 publications

References 49 publications

Genetic and pharmacological targeting of A2a receptor improves function of anti-mesothelin CAR T cells

Genetic and pharmacological targeting of A2a receptor improves function of anti-mesothelin CAR T cells

Cancer stem cells (CSCs) in cancer progression and therapy

Contribution of regulatory T cells to cancer: A review

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