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course 4_slides Flashcards

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1
Q

Describe the metastatic cascade in the context of tumor biology.

A

The metastatic cascade refers to the series of steps that cancer cells go through to spread from the primary tumor to other parts of the body.

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2
Q

What is cytokine-based anti-tumor therapy?

A

Cytokine-based anti-tumor therapy involves using cytokines, which are small proteins involved in cell signaling, to stimulate the immune system to target and destroy cancer cells.

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3
Q

Define oncolytic viruses in the context of tumor therapy.

A

Oncolytic viruses are viruses that are designed to infect and kill cancer cells while leaving normal cells unharmed, and they are being investigated as a potential treatment for tumors.

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4
Q

Describe the metastatic cascade.

A

The metastatic cascade involves the process of invasion, intrasation, production of systemic factors, establishing-metastatic niche, angiogenesis at the primary tumor, extravasation, persistent growth, adhesion, and immune evasion at the metastatic site.

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5
Q

Define intravasation in the context of metastatic tumors.

A

In the context of metastatic tumors, intravasation refers to the process by which cancer cells invade blood vessels and enter the bloodstream, allowing them to travel to distant sites in the body.

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6
Q

How does the production of systemic factors contribute to the development of metastatic tumors?

A

The production of systemic factors by the primary tumor contributes to the development of metastatic tumors by preparing the distant sites for the arrival and growth of metastatic cells, creating a favorable environment known as the pre-metastatic niche.

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7
Q

Describe the role of immune evasion in the context the primary tumor preparation for a metastatic journey.

A

The primary tumor prepares for metastasis by evading the immune system, involving factors such as CXCL5, CXCL6, CXCL8, and HMGB1, as observed in Kitamura et al.’s research in Nat Immunol. 2015.

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8
Q

What are the components involved in the preparation of the pre-metastatic niche for metastatic sites?

A

The pre-metastatic niche is prepared by attracting immature myeloid cells, TAMs (tumor-associated macrophages), Tregs (regulatory T cells), and matrix remodeling, along with the systemic release of factors and the expression of chemotactic factors and adhesion.

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9
Q

Describe the role of TAMs, TANs, MDSCs, and Treg cells in immune suppression within the primary tumor.

A

These cells directly suppress the cytotoxic functions of natural killer (NK) cells and CD8+ T cells through the production and expression of various factors.

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10
Q

Define the function of B7-H4 in immune suppression within the primary tumor.

A

B7-H4 binds an unknown receptor on activated T cells resulting in inhibition of T-cell effector function via cell cycle arrest, decreased proliferation, and reduced IL-2 production.

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11
Q

How do Treg cells utilize betaGBP to control CD8(+) T cell responses?

A

Treg cells express and utilize betaGBP to control CD8(+) T cell responses, as betaGBP interactions partially activate TCR signaling but block PI3K activity.

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12
Q

Describe the role of Breg cells in immune suppression within the primary tumor.

A

Breg cells are immunosuppressive cells that support immunological tolerance through the production of interleukin-10 (IL-10), IL-35, and transforming growth factor β (TGF-β), suppressing immunopathology.

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13
Q

Do MDSCs play a role in recruiting T helper 17 (TH17) cells? If so, how?

A

Yes, MDSCs secrete interleukin-6 (IL-6), IL-23, and TGFβ that recruit T helper 17 (TH17) cells, which in turn secrete IL-17, promoting the recruitment of MDSCs and the secretion of granulocyte colony-stimulating factor (G-CSF) from cancer-associated fibroblasts (CAFs).

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14
Q

Describe the role of primary tumors in preparing the preetastatic niche.

A

Primary tumors produce systemic factors that induce various changes in the metastatic sites before the arrival of tumor cells, including chemotactic protein expression, extracellular matrix remodeling, and recruitment of immature myeloid cells.

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15
Q

What is the function of LOX (lysyl oxidase) released by the primary tumor in the pre-metastatic niche?

A

LOX crosslinks collagen IV, promoting adhesion of CD11b+ cells in the pre-metastatic niche.

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16
Q

How are immature myeloid cells recruited to the pre-metastatic niche?

A

Immature myeloid cells are recruited to the pre-metastatic niche by expressing very late antigen 4 (VLA4) and being recruited to the niche by its ligand fibronectin.

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17
Q

Define the role of TAMs and T Reg cells in the pre-metastatic niche.

A

TAMs and T Reg cells are recruited to the pre-metastatic niche by primary tumor-derived fibrin clots, CCL2, and CCL22, and they promote future metastasis.

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18
Q

What are the effects of systemic factors and exosomes from primary tumors on bone marrow cells?

A

Systemic factors and exosomes from primary tumors can mobilize bone marrow cells into the circulation, which are then recruited to the pre-metastatic sites.

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19
Q

Describe the function of CD11b+LY6C+ monocytes in the pre-metastatic niche.

A

CD11b+LY6C+ monocytes recruited via CCL2 enhance the pulmonary metastasis of B16 cells.

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20
Q

How do bone marrow-derived cells contribute to the pre-metastatic niche in the lung?

A

Bone marrow-derived cells recruited to the pre-metastatic lung form clusters, promote the adherence and growth of subsequently disseminating tumor cells, and secrete MMP9, which may promote tumor cell invasion.

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21
Q

Describe the role of angiogenic factors in the first steps of metastasis.

A

Angiogenic factors contribute to higher blood vessel density and the formation of leaky capillaries, facilitating the spread of tumor cells.

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22
Q

Define TMEM in the context of metastasis.

A

TMEM refers to the tumor microenvironment for metastasis, which provides a conducive environment for the spread of tumor cells.

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23
Q

What are the key factors mentioned in the context of metastasis in the provided content?

A

The key factors mentioned are CXCL5, CXCL6, CXCL8, HMGB1, CXCL12, and VEGF.

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24
Q

Describe the role of myeloid cells in the early steps of metastasis.

A

Myeloid cells, such as TAMs, TANs, and MDSC, contribute to the early steps of metastasis by promoting tumor cell migration, angiogenesis, and intravasation into blood vessels.

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25
What factors contribute to the pro-angiogenic transformation of TAMs?
TAMs become pro-angiogenic through their response to colony-stimulating factor 1 (CSF1) and angiopoietin 2 (ANG2), as well as by secreting vascular endothelial growth factor A (VEGFA).
26
How do cancer cells interact with TAMs near blood vessels to promote invasiveness?
Cancer cells secrete CSF1 to prompt TAMs to produce epidermal growth factor (EGF), which activates EGF receptor on cancer cells and increases their invasiveness.
27
Define the role of TAMs in promoting tumour cell egress and metastasis.
TAMs promote tumour cell egress and metastasis through the secretion of cytokines, extracellular matrix remodeling, and by creating a tumour microenvironment for metastasis (TMEM) near blood vessels.
28
What environmental factors contribute to the differentiation of macrophages into tumour-promoting TAMs?
Environmental factors, including interleukin-4 (IL-4) from CD4+ T cells or tumour cells, promote the differentiation of macrophages into tumour-promoting TAMs that engage in the EGF–CSF1 paracrine loop and produce cathepsin proteinases, CCL18, and the extracellular matrix (ECM) regulator osteonectin to accelerate migration and intravasation of cancer cells.
29
Describe the role of MAM (metastasis associated macrophage) in the establishment of the metastatic niche.
MAM plays a crucial role in creating a favorable microenvironment for metastasis by promoting angiogenesis, extracellular matrix remodeling, and immune suppression.
30
Define the concept of the metastatic niche.
The metastatic niche refers to the specific microenvironment at a secondary site that supports the survival, growth, and colonization of metastatic cancer cells.
31
Describe the role of platelets, macrophages, and T Reg cells in protecting disseminating cancer cells from immune attack and the stress of a hostile environment.
Platelets, macrophages, and T Reg cells protect disseminating cancer cells by promoting clot formation, recruiting macrophages, and delivering survival signals to the cancer cells.
32
How does clot formation promote the early survival of cancer cells at metastatic sites?
Clot formation shields cancer cells from NK cells, enhances tumor cell survival by recruiting macrophages, and activates endothelial cells to express VCAM1, supporting macrophage recruitment.
33
Define the rate-limiting processes for metastasis following tumour egress.
The rate-limiting processes for metastasis following tumour egress include survival, extravasation, and metastatic growth.
34
What are the roles of TAMs, T Reg cells, and TANs in promoting the survival and entrapment of circulating cancer cells?
TAMs and T Reg cells deliver survival signals to cancer cells, while TANs enhance entrapment of circulating cancer cells by producing neutrophil extracellular traps (NETs).
35
Describe the role of MAMs in promoting extravasation of cancer cells at metastatic sites.
MAMs secrete VEGFA and increase vascular permeability, promoting extravasation of cancer cells.
36
How do platelets contribute to increasing vascular permeability following tumour extravasation?
Platelets increase vascular permeability following tumour extravasation by releasing A.
37
What are the steps involved in the establishment of metastatic foci by arrested tumour cells?
The steps involved in the establishment of metastatic foci include survival, extravasation, and metastatic growth at distant sites.
38
Describe the effect of recombinant cytokine expression in tumor cells on in vivo tumor growth.
Recombinant cytokine expression in tumor cells can lead to tumor rejection in animals, inflammatory infiltrate, and immunity against parental tumor.
39
Define IL-2 and its role in tumor rejection.
IL-2 is a cytokine that can lead to T cell-mediated immunity against tumors, involving lymphocytes and neutrophils. It has shown effectiveness in some cases of renal cancer and melanoma.
40
How does IL-4 impact tumor rejection and immunity in clinical trials?
IL-4 can lead to tumor rejection by involving eosinophils and macrophages. However, it has shown no long-lasting immunity in human trials for renal cancer and melanoma.
41
Do GM-CSF and IL-12 contribute to long-lived T cell immunity in tumor rejection?
Yes, both GM-CSF and IL-12 have been shown to contribute to long-lived T cell immunity in tumor rejection, with GM-CSF being effective in renal cancer cases.
42
Describe the function of IL2 (Aldleukin)
IL-2 is a growth factor for T cells and NK cells, and it also activates NK cells. It acts as an immune stimulator by increasing CXCR3 expression on CTL and NK cells.
43
What is the role of IL-2 (Aldesleukin) in the immune system?
IL-2 (Aldesleukin) acts as a growth factor for T cells and NK cells, activates NK cells, and stimulates the immune system by increasing CXCR3 expression on CTL and NK cells.
44
Describe the Phase II tumor vaccination process for hepatocellular carcinoma patients.
The Phase II tumor vaccination process for hepatocellular carcinoma patients involved administering three intradermal vaccinations at 2-week intervals, beginning 4–6 weeks after hepatic resection. The vaccinations included tumor lysate, IL-2, GM-CSF, and tuberculin.
45
What are the primary and secondary end points of the Phase II tumor vaccination study?
The primary end point of the Phase II tumor vaccination study is recurrence-free survival, while the secondary end point is overall survival.
46
How do microparticles contribute to the Phase II tumor vaccination process?
Microparticles deliver agents slowly, contributing to the gradual release of components in the vaccination process.
47
Define the role of GM-CSF in the Phase II tumor vaccination process.
GM-CSF activates intradermal APC (antigen-presenting cells), playing a role in the immune response during the vaccination process.
48
What is the purpose of using tuberculin in the Phase II tumor vaccination process?
Tuberculin serves as an adjuvant, specifically a TLR4 ligand, in the Phase II tumor vaccination process.
49
Describe the use of IL-2 in the of melanoma.
IL-2 is used as a treatment for melanoma, as discussed in the Cancer Immunol Immunother 2011 article.
50
What are the potential changes observed in patients with melanoma before and after IL-2 therapy?
The article discusses the changes observed in patients with melanoma before and after IL-2 therapy, as documented in the Cancer Immunol Immunother 2011 publication.
51
Describe the function of IL-2 (Aldleukin)
IL-2 is a T cell and NK cell growth factor that also activates NK cells and stimulates CXCR3 expression on CTL and NK cells.
52
What are the FDA-approved uses of IL-2 (Aldesleukin)?
IL-2 (Aldesleukin) is approved for metastatic melanoma and renal cell carcinoma, with a 6-7% complete response rate.
53
How is IL-2 (Aldesleukin) used in adoptive T cell therapy?
IL-2 (Aldesleukin) is used as an adjuvant in adoptive T cell therapy to promote the survival and proliferation of transplanted T cells.
54
What are some potential side effects of IL-2 (Aldesleukin)?
IL-2 (Aldesleukin) may have side effects and act as a survival factor for Treg, potentially promoting autoimmunity.
55
Describe adoptive T cell transfer (ACT) and its different approaches for treating cancer.
ACT involves transferring T cells to harness the immune system to treat cancer. This can be done by isolating tumor-infiltrating T cells (TILs) from a patient's tumor, expanding them in vitro, and re-infusing them into the patient. Alternatively, T cells from the patient's peripheral blood can be isolated, expanded in culture, and genetically modified to express a T cell receptor (TCR) or a chimeric antigen receptor (CAR) for specific tumor cell recognition and destruction.
56
What are tumor-infiltrating T cells (TILs) and how are they used in adoptive T cell transfer (ACT)?
TILs are T cells extracted from surgically resected tumor samples. In ACT, TILs are expanded in vitro and then re-infused into the lymphodepleted patient to harness the immune system to treat cancer.
57
How are T cells from a patient's peripheral blood used in adoptive T cell transfer (ACT) for treating cancer?
T cells from a patient's peripheral blood are isolated, expanded in culture, and genetically modified to express either a T cell receptor (TCR) or a chimeric antigen receptor (CAR) that enables them to specifically recognize and destroy tumor cells when re-infused into the lymphodepleted patient.
58
Describe the immunomodulatory effect of IFNa2.
IFNa2 has an immunomodulatory effect, as it can modulate the immune system (see figure below).
59
Define the FDA/EMA approved uses of IFNa2.
IFNa2 is approved by the FDA/EMA for resected melanoma at high risk of recurrence, Kaposi sarcoma, CML, non-Hodgkin’s lymphoma, and hairy cell leukemia.
60
How does IFNa2 exhibit angiostatic activity?
IFNa2 exhibits angiostatic activity by downregulating angiogenic growth factors and upregulating angiostatic IFN-inducible CXCR3 ligands.
61
Do all treated patients show prolonged therapy benefit from IFNa2?
No, only a subset of treated patients show prolonged therapy benefit from IFNa2, highlighting the need for markers that can predict response.
62
What study is the source of this information about IFNa2?
The information about IFNa2 is from the study by Zitvogel et al. 2015.
63
Describe the process of reversing the immunosup microenvironment in established tumors dominated by MDSCs.
Injecting the RIG-I ligand 5′-triphosphate RNA (3pRNA) complexed to invivo transfecting agents such as polyethylenimine directly into the tumor mass triggers the cytoplasmic innate immune sensor RIG-I in MDSCs, inducing strong type I IFN production and causing their differentiation into effective antigen-presenting cells.
64
How does 3pRNA trigger the reversal of the immunosuppressive microenvironment in established tumors?
3pRNA triggers the cytoplasmic innate immune sensor RIG-I in MDSCs, inducing strong type I IFN production and causing their differentiation into effective antigen-presenting cells.
65
Define the role of IFNα in the reversal of the immunosuppressive microenvironment in established tumors.
IFNα produced by MDSCs causes their differentiation into effective antigen-presenting cells, terminates the cytokine-dependent reciprocal NF-kB signaling loop between tumor cells and MDSCs, and supports strong T cell effector function in the tumor microenvironment.
66
What is the impact of 3pRNA entering tumor cells in the reversal of the immunosuppressive microenvironment?
3pRNA entering tumor cells triggers their RIG-I sensor, leading to tumor cell apoptosis and the release of tumor-associated antigens, which can be taken up by locally differentiated antigen-presenting cells to induce effective T cell activation against these antigens.
67
Describe the use of IFNalpha in angiostatic therapy.
IFNalpha is an approved drug for hepatitis and viral infections, and was first used as an angiostatic drug in hemangioma in children.
68
What type of tumors is IFNalpha effective for in angiostatic therapy?
IFNalpha is effective for tumors that rely on bFGF.
69
Define angiostatic therapy and provide an example of its application.
Angiostatic therapy involves the inhibition of blood vessel formation to restrict tumor growth. An example of its application is the use of IFNalpha in treating hemangioma in children.
70
Describe the mechanisms of action of IL12.
IL12 attracts myeloid cells (monocytes, macrophages, dendritic cells) and increases tumor lysis.
71
What are the effects of IL12 on myeloid cells?
IL12 attracts myeloid cells such as monocytes, macrophages, and dendritic cells.
72
How does IL12 impact tumor lysis?
IL12 increases tumor lysis.
73
Describe the structure of NHS-IL12.
NHS-IL12 consists of two molecules of IL-12 fused to a human IgG1 recognizing DNA/histone complexes, which are often exposed in the necrotic portions of tumors.
74
What are the advantages of using NHS-IL12 over recombinant IL-12 (rIL-12)?
NHS-IL12 has a longer plasma half-life compared to rIL-12 and is stronger in enhancing the proliferation and activation of immune as well as antigen-presenting cells, leading to a more robust immune response.
75
How does NHS-IL12 impact the tumor microenvironment (TME)?
NHS-IL12 reduces the number and function of suppressive myeloid cells (myeloid derived suppressor cells/macrophages) within the TME and reduces tumor growth in a murine bladder tumor model.
76
What are some potential combination therapies for NHS-IL12?
NHS-IL12 can be combined with other immune therapies (e.g. immune checkpoint inhibitors) and chemotherapy to increase overall anti-tumor efficacy in animal models.
77
What is the purpose of using NHS-IL12 in cancer treatment?
NHS-IL12 is designed for the delivery of IL-12 to the tumor microenvironment, aiming to reduce toxicity associated with systemic IL-12 and enhance anti-tumor immune responses.
78
Describe the role of chemokines in cancer.
Chemokines play a role in by influencing tumor growth factors, metastasis, modulation of angiogenesis/angiostasis, local tumor invasion, and leukocyte chemoattractants which can lead to either anti-tumor response or immune suppression.
79
What are the effects of chemokines on cancer progression?
Chemokines can influence tumor growth factors, metastasis, modulation of angiogenesis/angiostasis, local tumor invasion, and leukocyte chemoattractants, which can either promote an anti-tumor response or lead to immune suppression in the context of cancer.
80
How do chemokines impact the immune response in cancer?
Chemokines can influence the immune response in cancer by affecting leukocyte chemoattractants, which can lead to either anti-tumor response or immune suppression.
81
Describe the process of leukocyte adhesion.
Leukocyte adhesion involves increased integrin affinity, allowing the leukocyte to firmly 'stick' to the vessel wall.
82
What is the role of chemotactic activity in leukocyte function?
Chemotactic activity facilitates leukocyte extravasation and migration towards the source of chemokines.
83
Define leukocyte activation and provide an example of its immunological response.
Leukocyte activation involves protease release and can lead to immunological responses, such as in inflammation.
84
How do chemokine recruitment mechanisms guide leukocytes in the context of tumors?
Chemokine recruitment mechanisms guide both anti-tumoral and immune-suppressive leukocytes to the tumor.
85
What are the effects of chemokines on leukocytes?
Chemokines can have various effects on leukocytes, including guiding them towards specific locations and influencing their function in immunological responses.
86
Describe the role chemokines in attracting anti-tumoral immune cells to tumors.
Chemokines play a crucial role in attracting anti-tumoral immune cells to tumors. They are involved in innate immunity by attracting M1 macrophages, N1 neutrophils, and NK cells, as well as in adaptive immunity by attracting APC, CD4+ Th cells, and CD8+ CTL.
87
What are the types of immune cells attracted to tumors by chemokines in innate immunity?
In innate immunity, chemokines attract M1 macrophages (CC chemokines), N1 neutrophils (CXCR1/2 ligands), and NK cells (CXCR3 ligands) to tumors.
88
How do chemokines contribute to adaptive immunity in the context of tumor attraction?
In the context of tumor attraction, chemokines contribute to adaptive immunity by attracting APC (CC chemokines attracting imDC), CD4+ Th cells (CC chemokines), and CD8+ CTL (CC chemokines, CXCR3 ligands) to tumors.
89
Describe the role of chemokines in attracting pro-tumoral/immunosuppressive immune cells to tumors.
Chemokines play a role in attracting M2 macrophages, N2 neutrophils, myeloid-derived suppressor cells (MDSC's), and Treg cells to the tumor microenvironment, contributing to immunosuppression and tumor progression.
90
Define the immunosuppressive tumor microenvironment.
The immunosuppressive tumor microenvironment refers to the conditions within a tumor that promote immune evasion and suppression, often characterized by the presence of pro-tumoral/immunosuppressive immune cells and the secretion of immunosuppressive factors.
91
How do chemokines contribute to the attraction of immune cells to tumors in the context of innate immunity?
In the context of innate immunity, chemokines attract M2 macrophages (via CC chemokines), N2 neutrophils (via CXCR1/2 ligands), and myeloid-derived suppressor cells (MDSC's) (via CC chemokines and CXCR1/2 ligands) to the tumor microenvironment, contributing to immunosuppression and tumor progression.

immunology (11 decks)

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