Tumour immunology Flashcards
Can tumours be immunogenic?
Yes, this is proven through experiments where injecting a chemical carcinogen in a mouse induces tumour growth. If tumour cells are grown in the lab and injected into a naïve mouse, it will develop a tumour. However if irradiated tumour cells are used to vaccinate a naïve mouse, it remains tumour-free when challenged with live tumour cells. This shows tumours can be immunogenic.
Can tumours induce immunological memory?
Yes, if a tumour is induced in a mouse and then surgically resected, the cultured tumour cells can be injected into a naïve animal, which will develop a tumour. However, if injected into the original host, it remains tumour-free, demonstrating that tumours can induce immunological memory.
Which immune cells play a key role in immune memory?
T cells play a key role in immune memory. Tumour protection is not seen in T cell-deficient mice, and immune protection can be transferred by T cells from immune mice. Other immune cells like NK cells and macrophages also contribute to tumour immunology.
What is the evidence of tumour protective immunity being present in humans?
Evidence includes that immunosuppressed individuals develop cancer more frequently than immunocompetent individuals, and the presence of immune cells in tumours correlates with improved prognosis, such as in colorectal cancer.
What is the concept of immunosurveillance and immunoediting?
This concept predicts that the immune system can recognize and destroy cancer precursors before they become clinically apparent. It has been refined to state that the immune system not only protects against tumour development but also sculpts the immunogenicity of tumours, leading to the term ‘Cancer Immunoediting.’
What are the 3 E’s of cancer immunoediting?
- Elimination: Immune-mediated destruction of most cancer cells. 2. Equilibrium: A dynamic balance between the immune system and surviving tumour cell variants. 3. Escape: Tumour cell variants grow out in an environment where the immune system can no longer control them.
What is required for naive T cell activation?
- Target cells express antigenic peptides with MHC at the cell surface, engaging the TCR. 2. A second signal is provided by CD28 on the T cell interacting with CD80 or CD86 on the target cell.
What are some negative co-stimulation molecules of T cells?
Negative co-stimulation occurs when CTLA-4 on T cells outcompetes CD28 for binding to CD80/86, turning off the T cell. Other negative co-stimulators include PD1 receptor interacting with PD-L1/2.
Describe a successful T cell response to cancer.
A successful T cell response involves antigen release at the tumour site, uptake by dendritic cells, presentation to T cells in lymph nodes, clonal expansion, and migration to the tumour site to destroy malignant cells.
What are some types of tumour-associated antigens?
- Mutated self-proteins (e.g., cyclin-dependent kinase in melanoma). 2. Aberrantly or overexpressed self-proteins (e.g., CEA, AFP). 3. Lineage specific antigens (e.g., Mart1/Melan A in melanoma). 4. Abnormal post-translational modifications (e.g., MUC1 in breast cancer). 5. Viral proteins (e.g., HPV in cervical cancer).
What makes a good target antigen for tumour immunotherapy?
- Tumour-specific to reduce toxicity. 2. Shared among patients for wider applicability. 3. Critical for tumour growth/survival to prevent antigen-loss variants. 4. Lack of immunological tolerance to promote a strong T-cell response.
What are the 2 types of tolerance?
- Central Tolerance. 2. Peripheral Tolerance. These protect against autoimmunity.
What are the 2 types of tolerance?
Central Tolerance and Peripheral Tolerance
They protect against autoimmunity.
Describe the process of central tolerance and where it occurs.
Central tolerance occurs during T cell development in the thymus, involving positive and negative selection of T cells. T cells that cannot interact with MHC or react to self-antigens are deleted.
Only T cells capable of seeing antigens without reacting to self-tissue are released.
What is peripheral tolerance?
Peripheral tolerance is a backup mechanism for central tolerance, inactivating any auto-reactive T-cells that escape the thymus when they engage their target antigen in the absence of co-stimulation.
Such T-cells undergo anergy.
Why does tolerance pose a significant hurdle for successful tumour immunotherapy?
Central and peripheral tolerance mechanisms prevent the immune system from attacking self-tissue, but they also hinder tumour immunotherapy since cancer develops from the body’s own cells, making the immune system tolerant to most tumour antigens.
Describe the MHC class I processing pathway.
Proteins are synthesized in the cytosol, broken down into peptide fragments by the proteasome, and transported into the ER by TAP where they associate with MHC molecules. If the peptides fit the binding groove, they travel to the cell surface.
This allows TCR engagement.
What molecules (other than MHC) are required for T cell recognition?
TCR engagement with APC/Tumour cells is stabilized by adhesion molecules like LFA-1 on T cells and ICAM 1 & 2 on target cells.
Interference with these mechanisms can prevent T cells from detecting tumour cells.
Describe some mechanisms by which cancer cells might escape the immune response.
- Loss of HLA class I expression. 2. Reduced expression of antigen processing molecules (e.g., TAP1). 3. Loss of costimulatory molecules (e.g., CD80). 4. Loss of adhesion molecules (e.g., ICAM1). 5. Loss of target antigens. 6. Tumours inhibiting T cell infiltration. 7. Immunosuppression at tumour site.
How do T-reg cells work at the tumour site?
Regulatory T cells inhibit immune responses by influencing other cell types through cytokine release and direct contact. They are important for controlling responses to self-antigens and may play a role in tumour immune escape.
Regulatory T cells are defined by expression of which markers?
Regulatory T cells express CD4+, FoxP3+, CD25+, and CD127-.
FoxP3 is a transcriptional repressor.
What are myeloid-derived suppressor cells (MDSCs)?
MDSCs are a heterogeneous population of myeloid origin that expand during cancer and inflammation, suppressing T cell function and expressing immune suppressive factors like Arginase 1 and iNOS.
What are the 3 types of T cell-based therapies for cancer?
- Non-specific T cell stimulation. 2. Vaccination. 3. Adoptive T cell therapy.
Describe non-specific T cell stimulation.
It involves using immunostimulatory cytokines (e.g., IL2) and immune checkpoint inhibitors to boost T cell responses against tumours.
This can lead to increased survival in some patients.
