The latest developments in the rapidly evolving field of cancer research give us reason to be hopeful about the future. This collection of research papers from the five member journals of the Science journal family highlights progress in improving immunotherapy, enhancing drug delivery, identifying new therapeutic targets, understanding the tumor microenvironment and improving patient response . The Bibliography Editorial Department will briefly interpret all 10 papers in this special issue for everyone to learn and exchange.
1. Science : Vaccine combined with CAR-T cells to overcome the bottleneck of solid tumor treatment
Chimeric antigen receptor (CAR) -T cell immunotherapy has been very successful in treating certain blood cancers. However, this method has always been a challenge for solid tumors, in part because it is difficult to target functionally modified T cells to the tumor site. MIT Darrell J. Irvine et al. Designed a vaccine strategy to increase CAR-T cell efficacy by restimulating CAR directly in the natural lymph node microenvironment. The injected "amph-ligand" vaccine can promote the presentation of synthetic antigens and lead to the activation, expansion and increased tumor lethality of CAR-T cells. The system may be used to enhance any CAR-T cells.
Ma L, et al. Enhanced CAR–T cell activity against solidtumors by vaccine boosting through the chimeric receptor. Science.2019; 365 (6449): 162-8. DOI: 10.1126 / science.aav8692 https: //science.sciencemag. org / content / 365/6449/162
2. Science : Cancer evades targeted therapy through DNA mutations
Doctors treating bacterial infections and doctors treating cancer often face a common challenge: the development of drug resistance. It is well known that when bacteria are exposed to antibiotics, they temporarily increase their mutation rate (adaptive variability), thereby increasing the chance of the emergence of antibiotic-resistant cells in the offspring. So, do cancer cells use similar mechanisms to ensure that they survive after drug exposure? Because the general view is that tumor resistance is a fait accompli: when the treatment begins, the cancer already contains drug-resistant mutant cells. In view of this, Alberto Bardelli and Mariangela Russo of the Candiolo Cancer Institute in Italy studied whether human colorectal cancer (CRC) cells also use adaptive variability of similar bacteria to escape treatment pressure. They found that the epidermal growth factor receptor (EGFR) / BRAF inhibitor down-regulated the mismatch repair (MMR) and homologous recombination DNA repair genes, and at the same time up-regulated the error-prone polymerase in the resistant cells. During treatment, MMR protein was also down-regulated in patient-derived xenografts and tumor specimens. EGFR / BRAF inhibitors cause DNA damage, increased variability, and trigger microsatellite instability. Therefore, like bacteria, cancer cells can adapt to treatment pressure by enhancing their variability.
RussoM, Crisafulli G, Sogari A, Reilly NM, Arena S, Lamba S, et al. Adaptivemutability of colorectal cancers in response to targeted therapies. Science.2019; 366 (6472): 1473-80. DOI: 10.1126 / science.aav4474 https://doi.org/10.1126/science.aav4474
3. Science Advances : High-efficiency tumor-selective nanoparticles for dual-targeted tumor immunotherapy
Although immunotherapy has broad prospects in fighting cancer, the limited efficacy of immunosuppressive tumor microenvironment and systemic toxicity has hindered the widespread application of cancer immunotherapy. Here, Chen Yunjing of National Tsinghua University in Taiwan and Shu-Yi Lin of the National Institute of Health in Taiwan reported a combination immunotherapy that uses highly efficient and tumor-selective gene carriers to improve anti-cancer efficacy and avoid systemic toxicity. In this study, tumor-targeted lipid dendrimer calcium phosphate (TT-LDCP) nanoparticles (NPs) with thymine-functionalized dendrimers were designed. The factor (STING) cGAS pathway not only shows enhanced gene delivery capabilities, but also has immune adjuvant properties. TT-LDCP NPs deliver siRNA against hepatocellular carcinoma (HCC) against the immune checkpoint ligand PD-L1 and immunostimulatory IL-2 encoding plasmid DNA, increasing tumor infiltration and CD8 + T cell activation, enhancing cancer vaccines The effectiveness of immunotherapy and inhibited HCC growth. This work proposes the dual delivery of siRNA and plasmid DNA achieved by nanotechnology, which can selectively target and reprogram the immune suppression tumor microenvironment to improve cancer immunotherapy.
HuangK-W, et al. Highly efficient and tumor-selective nanoparticles for dual-targeted immunogene therapy against cancer. Science Advances.2020; 6 (3): eaax5032. DOI: 10.1126 / sciadv.aax5032 https://advances.sciencemag.org / content / 6/3 / eaax5032
4. Science Advances : tracking phenotype changes of extracellular vesicles can monitor the treatment of melanoma
Real-time monitoring of targeted therapies for cancer patients can provide important information about drug resistance development and improved treatment outcomes. Extracellular vesicles (EVs) have recently become promising cancer biomarkers, and the EV phenotype shows great potential for monitoring treatment response. Here, Matt Trau of the University of Queensland in Australia and Yuling Wang of Macquarie University demonstrated the feasibility of using multiple EV phenotype analyzer chips (EPAC) to monitor the treatment response of patients based on the evolution of plasma EV phenotype. EPAC combines nano-hybrid enhanced microchips and multiple surface enhanced Raman scattering (SERS) nanotag systems for direct EV phenotyping without the need for EV enrichment. In the preclinical model, the researchers observed EV phenotypic heterogeneity and different phenotypic responses to treatment. In addition, the researchers successfully detected cancer-specific EV phenotypes from the plasma of melanoma patients. Longitudinal monitoring of the EV phenotype evolution of eight melanoma patients receiving targeted therapy and found specific EV profiles related to the development of drug resistance, reflecting the potential of EV phenotype to monitor treatment response.
WangJ, et al. Tracking extracellular vesicle phenotypic changes enables treatment monitoring in melanoma. Science Advances. 2020; 6 (9): eaax3223. DOI: 10.1126 / sciadv.aax3223 https://advances.sciencemag.org/content/6/9/ eaax3223
5. Science Immunology : Targeted deletion of PD-1 in myeloid cells can induce anti-tumor immunity
Immunotherapy against programmed cell death protein 1 (PD-1), which can reverse T cell depletion, has revolutionized cancer treatment. PD-1 is a T cell checkpoint receptor, a target for cancer immunotherapy, and can also be expressed on myeloid cells. The role of myeloid-specific and T-cell-specific PD-1 ablation in anti-tumor immunity is unclear, because most studies have used PD-1 blocking antibodies or intact PD-1 KO mice. Here, by generating Pdcd1 floxed mice and conditionally deleting PD-1 in T cells or bone marrow cells, Vassiliki A. Boussiotis et al. Of Harvard Medical School discovered PD-1 in myeloid cells that were not previously recognized The anti-tumor immunity is inhibited by overexpression. They found that selective excision of PD-1 in myeloid cells limits the growth of tumors as effectively as the absence of PD-1, and has demonstrated the importance of PD-1 in regulating the development and function of myeloid cells. Although the study did not question the role of PD-1 in T cell depletion, the results require people to rethink how PD-1 centered therapy works.
Strauss L, et al. Targeted deletion of PD-1 in myeloid cellsinduces antitumor immunity. Science Immunology. 2020; 5 (43): eaay1863. DOI: 10.1126 / sciimmunol.aay1863 https://immunology.sciencemag.org/content/5 / 43 / eaay1863
6. Science Immunology : reveal the mechanism of CAR-T therapy causing inflammatory factor storm
Cytokine release syndrome (CRS) is a complication associated with chimeric antigen receptor (CAR) T cell therapy for cancer patients. The mechanism that triggers CRS is unclear, but Professor Huang Bo and others from the Institute of Basic Medical Sciences , Chinese Academy of Medical Sciences and others described the role of the pore-forming protein Gasdermin E (GSDME) during the pyrolysis of tumor cells, which helps CRS. CART cells release granzyme B, which activates caspase 3 and cleaves GSDME in target tumor cells and causes pyrolysis. GSDME-induced cell pyrolysis causes the activation of caspase 1 and GSDMD in macrophages, which is essential for triggering CRS. The increase of GSDME level in cancer patients is positively correlated with the severity of CRS. In addition, the ability of CAR T cells to induce pyroptosis is related to the levels of perforin and granzyme B released.
LiuY, et al. Gasdermin E–mediated target cell pyroptosis by CAR T cells triggerscytokine release syndrome. Science Immunology. 2020; 5 (43): eaax7969. DOI: 10.1126 / sciimmunol.aax7969 https://immunology.sciencemag.org/content / 5/43 / eaax7969
7. Science Signaling : Systematic mechanism of allele-specific response to KRAS mutant targeted therapy
Colorectal cancer (CRC) patients expressing the KRAS G13D mutant usually respond to the blockade of the growth factor receptor EGFR, while CRC patients with all other KRAS mutants do not. Because the reason why this treatment works in the context of known EGFR-RAS biology is unclear, clinical practice generally refuses to use it in all patients with KRAS mutant CRC. However, Edward C. Stites and others of the Salk Institute of Biology in the United States used comprehensive calculations and biochemical methods to show that compared with other KRAS mutant proteins, the interaction of KRAS G13D with protein NF1 is too weak to competitively inhibit it; Therefore, wild-type RAS in KRAS G13D cells still depends on EGFR activation and for tumor growth. These findings reveal why precision medicine will benefit more patients at the system level rather than the genome level.
McFallT, et al. A systems mechanism for KRAS mutant allele–specific responses totargeted therapy. Science Signaling. 2019; 12 (600): eaaw8288. DOI: 10.1126 / scisignal.aaw8288 https://stke.sciencemag.org/content/12 / 600 / eaaw8288
8. Science Signaling : Adipocytes can trigger tumor metastasis
In samples from melanoma patients, the tumors appear to grow in the lateral hyperplasia of the epidermal layer on the skin, but when they grow to deeper layers where fat (fat) is present, they transition to a vertical infiltration period. Carmit Levy et al. Of Tel Aviv University in Israel studied the co-culture of melanoma cells and adipocytes and determined the direct role of adipocytes in this metastatic conversion. The authors found that adipocytes secrete cytokines and send signals through receptors on melanoma cells, thereby suppressing the expression of microRNAs that promote proliferation and inhibit aggressive phenotypes. MicroRNA also inhibits the expression of the receptor for growth factor TGF-β, which is associated with metastatic disease and is abundant in the dermis. Blocking TGF-β signaling prevents the invasive conversion of cultured melanoma cells, and therefore can inhibit the metastasis of patients.
Golan T, et al. Adipocytes sensitize melanoma cells toenvironmental TGF-β cues by repressing the expression of miR-211. ScienceSignaling. 2019; 12 (591): eaav6847. DOI: 10.1126 / scisignal.aav6847 https: //stke.sciencemag. org / content / 12/591 / eaav6847
9. Science Translational Medicine : Anti-cancer drugs may not work as we think
97% of the drug indication pairs tested in tumor clinical trials have never been approved by the US Food and Drug Administration. Although the lack of efficacy and dose-limiting toxicity are the most common causes of failed trials, the reason why so many new drugs encounter these problems is unclear. Using CRISPR-Cas9 mutation technology, ason M. Sheltzer and others at the Cold Spring Harbor Laboratory in the United States studied a series of anti-cancer drugs and drug targets at different stages of clinical trials. A potential cause of this problem was identified, indicating that certain compounds in clinical development did not actually target oncogenes that they were originally believed to target. Then, the researchers identified multiple drugs with similar problems and found the correct target for one of the drugs, which indicates that more research and more rigorous methods are needed to verify the potential of the drug before pushing it to the clinic target.
Lin A, et al. Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Science Translational Medicine.2019; 11 (509): eaaw8412. DOI: 10.1126 / scitranslmed.aaw8412 https: //stm.sciencemag. org / content / 11/509 / eaaw8412
10. Science Translational Medicine : Congenital Vδ1 + γδ T cells in human breast may help relieve triple negative breast cancer
It is known that specific subsets of γδ T cells can fill tissues such as skin and intestines. In order to determine that γδ T cells are involved in breast cancer monitoring, Adrian Hayday et al. At King‘s College London in the United Kingdom isolated cells from a mesh culture of human breast tissue. They observed cytolytic congenital Vδ1 + T cells in healthy human breast tissue and tumor tissue . Analysis of a small group of women with triple-negative breast cancer showed that these Vδ1 + T cells were associated with remission and overall survival. These results indicate that γδ T cells residing in human tissues may affect breast cancer progression. These cells may be the key to current or future immunotherapy interventions.
Wu Y, et al. An innate-like Vδ1 + γδ T cell compartment in the human breast is associated with remission in triple-negative breast cancer. Science Translational Medicine. 2019; 11 (513): eaax9364. DOI: 10.1126 / scitranslmed.aax9364 https : //stm.sciencemag.org/content/11/513/eaax9364
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