Cancer Moonshot - inmunoterapia

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Sab, 28 Ene 2017, 09:17

Las células T regulatorias ejercen acción inmunosupresiva mediante distintos mecanismos.
Antibodies that block checkpoint receptors, such as the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1), have shown remarkable clinical effects. However, durable responses to checkpoint blockers have been obtained in only a fraction of patients [1], suggesting that persistence of immunosuppressive mechanisms may contribute to intrinsic resistance to cancer immunotherapy.

Cells in the tumor microenvironment attributed with immunosuppressive activities include cancer-associated fibroblasts, myeloid-derived suppressor cells, and CD4+ regulatory T (Treg) cells expressing the transcription factor FOXP3. Specifically, Treg cells play an essential role in suppressing aberrant immune responses against self-antigens and anti-tumor immune responses. Treg cells are potent suppressors of effector T cells, and, consequently, increased densities of tumor-infiltrating Treg cells have been associated with poor prognosis in a number of cancers
Treg cells can suppress effector T cells through different direct mechanisms, including secretion of inhibitory cytokines, granzyme-mediated cytolysis of effector T cells, and metabolic impairment of effector T cells—for example, by depletion of interleukin-12 (IL-12)—as well as indirect mechanisms such as suppression of dendritic cell maturation and function
Tumors with more aggressive phenotypes, such as triple-negative breast cancers (TNBCs), contained higher frequencies of Treg cells, which might imply an active role for Treg cells in cancer progression
RNA-sequencing analysis revealed marked transcriptomic differences between tumor- or tissue-resident Treg versus peripheral blood Treg cells, while
the gene expression profiles were highly comparable between Treg cells present in breast tumor and normal tissue
CCR8 es un buen candidato para inhibir la respuesta inmunosupresiva. Sin embargo se expresa en el corazón e hígado, por lo que podrían darse problemas autoinmunes.
marked expression of chemokine receptor 8 (CCR8), a molecule implicated in the modulation of immunogenicity in colorectal cancer (CRC) [6], was identified as a unique feature of intratumoral Treg cells
authors found a strong negative association between the ratio of CCR8/FOXP3-expressing cells and patient survival
Interesantemente los tumores que expresan mayor regulación al alza de respuesta inmunosupresora CTLA4, LAG3, TIM3 correlacionan con peor 5 YR survival.

https://genomemedicine.biomedcentral.co ... 017-0402-8
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Lun, 30 Ene 2017, 09:45

Mutación en el gen B2M como mecanismo de inmunorresistencia via HLA - MHC

https://immuno-oncologynews.com/2017/01 ... -response/
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Lun, 30 Ene 2017, 10:12

Cancers can directly inhibit immune reactivity by secreting soluble immune inhibitory mediators such as PGE2, TGF-b and IL-10

They also express checkpoint inhibitory ligands such as PD-L1 that block immune reactivity

Indirect immune inhibition by cancers is mediated by their in- duction of host immune inhibitory cell populations. These include macrophages, Treg cells, Th2 skewed T-cells, myeloid-derived suppressor cells (MDSC) and the less mature CD34 þ progenitor cells. There are not only inhibitory immune cell populations, but also immune inhibitory endothelial cells and fi broblasts
cancerletters.info/article/S0304-3835(17)30063-0/abstract?cc=y=
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Lun, 30 Ene 2017, 10:13

Macrófagos TAMs
Macrophages are crucial drivers of tumour-promoting inflammation. Tumour-associated macrophages (TAMs) contribute to tumour progression at different levels: by promoting genetic instability, nurturing cancer stem cells, supporting metastasis, and taming protective adaptive immunity. TAMs can exert a dual, yin–yang influence on the effectiveness of cytoreductive therapies (chemotherapy and radiotherapy), either antagonizing the antitumour activity of these treatments by orchestrating a tumour-promoting, tissue-repair response or, instead, enhancing the overall antineoplastic effect. TAMs express molecular triggers of checkpoint proteins that regulate T-cell activation, and are targets of certain checkpoint-blockade immunotherapies. Other macrophage-centred approaches to anticancer therapy are under investigation, and include: inhibition of macrophage recruitment to, and/or survival in, tumours; functional re-education of TAMs to an antitumour, 'M1-like' mode; and tumour-targeting monoclonal antibodies that elicit macrophage-mediated extracellular killing, or phagocytosis and intracellular destruction of cancer cells. The evidence supporting these strategies is reviewed herein. We surmise that TAMs can provide tools to tailor the use of cytoreductive therapies and immunotherapy in a personalized medicine approach, and that TAM-focused therapeutic strategies have the potential to complement and synergize with both chemotherapy and immunotherapy.
http://www.nature.com/nrclinonc/journal ... 6.217.html
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Lun, 30 Ene 2017, 22:40

Inhibidores de checkpoint en las plaquetas, directamente al tumor para disminuir problemas autoinmunes en el resto del organismo
The tiny blood cells, which gravitate to the surgical site to start the healing process, can be loaded with immune-checkpoint inhibitors to activate the immune system at the site. That approach will leave other organs and tissue unharmed.

The study, “In situ activation of platelets with checkpoint inhibitors for post-surgical cancer immunotherapy,” was published in Nature Biomedical Engineering.
“We wanted to utilize platelets’ intrinsic tendencies to accumulate at wounds and to interact with circulating tumor cells, for targeted delivery of immune checkpoint inhibitors”
https://immuno-oncologynews.com/2017/01 ... e-impacts/



Relación plaquetas células cancerígenas
Thrombocytosis is frequently observed in patients with metastatic cancers suggesting the important role of platelets in metastasis. Therefore this review focuses on how platelets facilitate the generation of CTCs, protect them from various host attacks, such as immune assaults, apoptosis and shear stress, and regulate CTCs intravasation/extravasation. Platelet-derived cytokines and receptors are involved in this cascade.
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Lun, 30 Ene 2017, 22:42

Esto me ha gustado mucho. Imagen funcional de CAR-T
have developed a method to map the physical distribution and expansion of infused T cells throughout the body, using a radiotracer that has already been approved by the FDA for use in imaging neuroendocrine tumors.
“The critical barrier to predicting toxicity is the inability to see where the T cells go in the patient’s body after injection,” Jin said. “There are a number of ways T-cell activities can be turned off quickly, but we need to know when to intervene.”
http://meyercancer.weill.cornell.edu/ne ... =hootsuite
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Mar, 31 Ene 2017, 12:32

El papel paradójico del estrés oxidativo. Seguimos sin saber muy bien lo que sucede aquí.
Intracellular ROS level is tightly controlled by various antioxidants. In contrast, cancer cells have an abnormally high level of ROS due to an increased ROS production and/or impaired ROS detoxification that can damage intracellular macromolecules such as nucleic acids, proteins, and lipids. Elevated ROS production in cancer cells may result from an aberrant metabolic activity, mitochondrial dysfunction, disturbed cellular signaling, oncogene activity, and interaction with tumor infiltrating immune cells.
emerging lines of evidence indicates that tumor cells also need to defend themselves from oxidative damage in order to survive and successfully spread at distance.

the transforming activity of some oncogenes has been unexpectedly linked to their capacity to maintain elevated intracellular levels of reduced glutathione (GSH), the principal redox buffer. These studies underline the importance of cellular antioxidant capacity in metastasis, as the result of a complex cell program involving enhanced motility and a profound change in energy metabolism. The glycolytic switch (Warburg effect) observed in malignant tissues is triggered by mitochondrial oxidative damage and/or activation of redox-sensitive transcription factors, and results in an increase of cell resistance to oxidants

we suggest that metastasis represents an integrated strategy for cancer cells to avoid oxidative damage and escape excess ROS in the primary tumor site, explaning why redox signaling pathways are often up-regulated in malignancy and metastasis.
https://www.ncbi.nlm.nih.gov/pubmed/20386957
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Mar, 31 Ene 2017, 12:47

Higher levels of ROS disrupt cellular processes by non-specifically attacking proteins, lipids, and DNA

The importance of ROS in driving cancer progression was demonstrated by Gao et al. (2007)), who administered the antioxidant N-acetyl cysteine (NAC) to mice carrying tumor xenografts. They observed a decrease in tumor growth that was traced to a redox-mediated attenuation in levels of the transcription factor, Hypoxia-Inducible Factor-1 (HIF-1)

in K-ras and B-raf-driven genetic models of lung cancer, Sayin et al. (2014)) found that NAC and vitamin E increased tumor cell proliferation by attenuating ROS, DNA damage, and p53 expression. These findings suggest that increases in ROS generation that develop as a cell becomes cancerous represent a potentially toxic byproduct of metabolic reprogramming and antioxidant defenses—or exogenous antioxidants—may enhance survival/progression by protecting the cell against the antiproliferative effects of those oxidant stresses
In that sense, tumor cells engage in a deadly dance where some oxidants contribute to mutation and growth while excessive stress slows proliferation and threatens survival
increased oxidant stress led to fewer tumors that progressed more slowly than those in mice with normal GSH. This suggests that increased oxidant stress was detrimental to the process of tumorigenesis and progression
cell.com/cancer-cell/fulltext/S1535-6108(15)00022-7
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Mar, 31 Ene 2017, 12:52

Antioxidantes atenuan la toxicidad inducida por quimioterapia
Impact of antioxidant supplementation on chemotherapeutic toxicity: A systematic review of the evidence from randomized controlled trials

33 of 965 articles considered, including 2,446 subjects, met the inclusion criteria. Antioxidants evaluated were: glutathione (11), melatonin (7), vitamin A (1), an antioxidant mixture (2), N-acetylcysteine (2), vitamin E (5), selenium (2), L-carnitine (1), Co-Q10 (1) and ellagic acid (1). The majority (24) of the 33 studies included reported evidence of decreased toxicities from the concurrent use of antioxidants with chemotherapy. Nine studies reported no difference in toxicities between the 2 groups. Only 1 study (vitamin A) reported a significant increase in toxicity in the antioxidant group. Five studies reported the antioxidant group completed more full doses of chemotherapy or had less-dose reduction than control groups. Statistical power and poor study quality were concerns with some studies. This review provides the first systematically reviewed evidence that antioxidant supplementation during chemotherapy holds potential for reducing dose-limiting toxicities. However, well-designed studies evaluating larger populations of patients given specific antioxidants defined by dose and schedule relative to chemotherapy are warranted
http://onlinelibrary.wiley.com/doi/10.1 ... 900.f02t01


Esto es muy interesante, puesto que podría proteger las células sanas del corazón, de los riñones y evitar así en parte la nefrotoxicidad y cardiotoxicidad de estos tratamientos que aumentan el riesgo cardiovascular, etc. Sin embargo, aunque este aspecto es positivo, podría proteger también a las células cancerígenas.

El problema aquí es el de siempre, que esto no se estudia rigurosamente. Y como no se estudia, vienen los bocazas deshonestos del hescepticismo con su discurso favorito: "no hay hebidencia".
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Mar, 31 Ene 2017, 21:34

No soy capaz de acceder a este paper, es interesante. Vacunas contra tumores, por qué su eficacia es modesta.
Cancer vaccine development has been vigorously pursued for 40 years. Immunity to tumor antigens can be elicited by most vaccines tested, but their clinical efficacy remains modest. We argue that a concerted international effort is necessary to understand the human antitumor immune response and achieve clinically effective cancer vaccines
https://www.ncbi.nlm.nih.gov/pubmed/27075624
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