course 4_slides

Question 1

Describe the metastatic cascade in the context of tumor biology.

Answer 1

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.

Question 2

What is cytokine-based anti-tumor therapy?

Answer 2

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.

Question 3

Define oncolytic viruses in the context of tumor therapy.

Answer 3

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.

Question 4

Describe the metastatic cascade.

Answer 4

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.

Question 5

Define intravasation in the context of metastatic tumors.

Answer 5

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.

Question 6

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

Answer 6

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.

Question 7

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

Answer 7

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.

Question 8

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

Answer 8

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.

Question 9

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

Answer 9

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

Question 10

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

Answer 10

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.

Question 11

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

Answer 11

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

Question 12

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

Answer 12

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.

Question 13

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

Answer 13

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).

Question 14

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

Answer 14

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.

Question 15

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

Answer 15

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

Question 16

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

Answer 16

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.

Question 17

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

Answer 17

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.

Question 18

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

Answer 18

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

Question 19

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

Answer 19

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

Question 20

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

Answer 20

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.

Question 21

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

Answer 21

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

Question 22

Define TMEM in the context of metastasis.

Answer 22

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

Question 23

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

Answer 23

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

Question 24

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

Answer 24

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.

Question 25

What factors contribute to the pro-angiogenic transformation of TAMs?

Answer 25

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).

Question 26

How do cancer cells interact with TAMs near blood vessels to promote invasiveness?

Answer 26

Cancer cells secrete CSF1 to prompt TAMs to produce epidermal growth factor (EGF), which activates EGF receptor on cancer cells and increases their invasiveness.

Question 27

Define the role of TAMs in promoting tumour cell egress and metastasis.

Answer 27

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.

Question 28

What environmental factors contribute to the differentiation of macrophages into tumour-promoting TAMs?

Answer 28

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.

Question 29

Describe the role of MAM (metastasis associated macrophage) in the establishment of the metastatic niche.

Answer 29

MAM plays a crucial role in creating a favorable microenvironment for metastasis by promoting angiogenesis, extracellular matrix remodeling, and immune suppression.

Question 30

Define the concept of the metastatic niche.

Answer 30

The metastatic niche refers to the specific microenvironment at a secondary site that supports the survival, growth, and colonization of metastatic cancer cells.

Question 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.

Answer 31

Platelets, macrophages, and T Reg cells protect disseminating cancer cells by promoting clot formation, recruiting macrophages, and delivering survival signals to the cancer cells.

Question 32

How does clot formation promote the early survival of cancer cells at metastatic sites?

Answer 32

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.

Question 33

Define the rate-limiting processes for metastasis following tumour egress.

Answer 33

The rate-limiting processes for metastasis following tumour egress include survival, extravasation, and metastatic growth.

Question 34

What are the roles of TAMs, T Reg cells, and TANs in promoting the survival and entrapment of circulating cancer cells?

Answer 34

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).

Question 35

Describe the role of MAMs in promoting extravasation of cancer cells at metastatic sites.

Answer 35

MAMs secrete VEGFA and increase vascular permeability, promoting extravasation of cancer cells.

Question 36

How do platelets contribute to increasing vascular permeability following tumour extravasation?

Answer 36

Platelets increase vascular permeability following tumour extravasation by releasing A.

Question 37

What are the steps involved in the establishment of metastatic foci by arrested tumour cells?

Answer 37

The steps involved in the establishment of metastatic foci include survival, extravasation, and metastatic growth at distant sites.

Question 38

Describe the effect of recombinant cytokine expression in tumor cells on in vivo tumor growth.

Answer 38

Recombinant cytokine expression in tumor cells can lead to tumor rejection in animals, inflammatory infiltrate, and immunity against parental tumor.

Question 39

Define IL-2 and its role in tumor rejection.

Answer 39

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.

Question 40

How does IL-4 impact tumor rejection and immunity in clinical trials?

Answer 40

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.

Question 41

Do GM-CSF and IL-12 contribute to long-lived T cell immunity in tumor rejection?

Answer 41

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.

Question 42

Describe the function of IL2 (Aldleukin)

Answer 42

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.

Question 43

What is the role of IL-2 (Aldesleukin) in the immune system?

Answer 43

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.

Question 44

Describe the Phase II tumor vaccination process for hepatocellular carcinoma patients.

Answer 44

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.

Question 45

What are the primary and secondary end points of the Phase II tumor vaccination study?

Answer 45

The primary end point of the Phase II tumor vaccination study is recurrence-free survival, while the secondary end point is overall survival.

Question 46

How do microparticles contribute to the Phase II tumor vaccination process?

Answer 46

Microparticles deliver agents slowly, contributing to the gradual release of components in the vaccination process.

Question 47

Define the role of GM-CSF in the Phase II tumor vaccination process.

Answer 47

GM-CSF activates intradermal APC (antigen-presenting cells), playing a role in the immune response during the vaccination process.

Question 48

What is the purpose of using tuberculin in the Phase II tumor vaccination process?

Answer 48

Tuberculin serves as an adjuvant, specifically a TLR4 ligand, in the Phase II tumor vaccination process.

Question 49

Describe the use of IL-2 in the of melanoma.

Answer 49

IL-2 is used as a treatment for melanoma, as discussed in the Cancer Immunol Immunother 2011 article.

Question 50

What are the potential changes observed in patients with melanoma before and after IL-2 therapy?

Answer 50

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.

Question 51

Describe the function of IL-2 (Aldleukin)

Answer 51

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.

Question 52

What are the FDA-approved uses of IL-2 (Aldesleukin)?

Answer 52

IL-2 (Aldesleukin) is approved for metastatic melanoma and renal cell carcinoma, with a 6-7% complete response rate.

Question 53

How is IL-2 (Aldesleukin) used in adoptive T cell therapy?

Answer 53

IL-2 (Aldesleukin) is used as an adjuvant in adoptive T cell therapy to promote the survival and proliferation of transplanted T cells.

Question 54

What are some potential side effects of IL-2 (Aldesleukin)?

Answer 54

IL-2 (Aldesleukin) may have side effects and act as a survival factor for Treg, potentially promoting autoimmunity.

Question 55

Describe adoptive T cell transfer (ACT) and its different approaches for treating cancer.

Answer 55

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.

Question 56

What are tumor-infiltrating T cells (TILs) and how are they used in adoptive T cell transfer (ACT)?

Answer 56

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.

Question 57

How are T cells from a patient’s peripheral blood used in adoptive T cell transfer (ACT) for treating cancer?

Answer 57

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.

Question 58

Describe the immunomodulatory effect of IFNa2.

Answer 58

IFNa2 has an immunomodulatory effect, as it can modulate the immune system (see figure below).

Question 59

Define the FDA/EMA approved uses of IFNa2.

Answer 59

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.

Question 60

How does IFNa2 exhibit angiostatic activity?

Answer 60

IFNa2 exhibits angiostatic activity by downregulating angiogenic growth factors and upregulating angiostatic IFN-inducible CXCR3 ligands.

Question 61

Do all treated patients show prolonged therapy benefit from IFNa2?

Answer 61

No, only a subset of treated patients show prolonged therapy benefit from IFNa2, highlighting the need for markers that can predict response.

Question 62

What study is the source of this information about IFNa2?

Answer 62

The information about IFNa2 is from the study by Zitvogel et al. 2015.

Question 63

Describe the process of reversing the immunosup microenvironment in established tumors dominated by MDSCs.

Answer 63

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.

Question 64

How does 3pRNA trigger the reversal of the immunosuppressive microenvironment in established tumors?

Answer 64

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.

Question 65

Define the role of IFNα in the reversal of the immunosuppressive microenvironment in established tumors.

Answer 65

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.

Question 66

What is the impact of 3pRNA entering tumor cells in the reversal of the immunosuppressive microenvironment?

Answer 66

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.

Question 67

Describe the use of IFNalpha in angiostatic therapy.

Answer 67

IFNalpha is an approved drug for hepatitis and viral infections, and was first used as an angiostatic drug in hemangioma in children.

Question 68

What type of tumors is IFNalpha effective for in angiostatic therapy?

Answer 68

IFNalpha is effective for tumors that rely on bFGF.

Question 69

Define angiostatic therapy and provide an example of its application.

Answer 69

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.

Question 70

Describe the mechanisms of action of IL12.

Answer 70

IL12 attracts myeloid cells (monocytes, macrophages, dendritic cells) and increases tumor lysis.

Question 71

What are the effects of IL12 on myeloid cells?

Answer 71

IL12 attracts myeloid cells such as monocytes, macrophages, and dendritic cells.

Question 72

How does IL12 impact tumor lysis?

Answer 72

IL12 increases tumor lysis.

Question 73

Describe the structure of NHS-IL12.

Answer 73

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.

Question 74

What are the advantages of using NHS-IL12 over recombinant IL-12 (rIL-12)?

Answer 74

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.

Question 75

How does NHS-IL12 impact the tumor microenvironment (TME)?

Answer 75

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.

Question 76

What are some potential combination therapies for NHS-IL12?

Answer 76

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.

Question 77

What is the purpose of using NHS-IL12 in cancer treatment?

Answer 77

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.

Question 78

Describe the role of chemokines in cancer.

Answer 78

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.

Question 79

What are the effects of chemokines on cancer progression?

Answer 79

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.

Question 80

How do chemokines impact the immune response in cancer?

Answer 80

Chemokines can influence the immune response in cancer by affecting leukocyte chemoattractants, which can lead to either anti-tumor response or immune suppression.

Question 81

Describe the process of leukocyte adhesion.

Answer 81

Leukocyte adhesion involves increased integrin affinity, allowing the leukocyte to firmly ‘stick’ to the vessel wall.

Question 82

What is the role of chemotactic activity in leukocyte function?

Answer 82

Chemotactic activity facilitates leukocyte extravasation and migration towards the source of chemokines.

Question 83

Define leukocyte activation and provide an example of its immunological response.

Answer 83

Leukocyte activation involves protease release and can lead to immunological responses, such as in inflammation.

Question 84

How do chemokine recruitment mechanisms guide leukocytes in the context of tumors?

Answer 84

Chemokine recruitment mechanisms guide both anti-tumoral and immune-suppressive leukocytes to the tumor.

Question 85

What are the effects of chemokines on leukocytes?

Answer 85

Chemokines can have various effects on leukocytes, including guiding them towards specific locations and influencing their function in immunological responses.

Question 86

Describe the role chemokines in attracting anti-tumoral immune cells to tumors.

Answer 86

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.

Question 87

What are the types of immune cells attracted to tumors by chemokines in innate immunity?

Answer 87

In innate immunity, chemokines attract M1 macrophages (CC chemokines), N1 neutrophils (CXCR1/2 ligands), and NK cells (CXCR3 ligands) to tumors.

Question 88

How do chemokines contribute to adaptive immunity in the context of tumor attraction?

Answer 88

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.

Question 89

Describe the role of chemokines in attracting pro-tumoral/immunosuppressive immune cells to tumors.

Answer 89

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.

Question 90

Define the immunosuppressive tumor microenvironment.

Answer 90

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.

Question 91

How do chemokines contribute to the attraction of immune cells to tumors in the context of innate immunity?

Answer 91

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.