Transcriptional immune profiles for cancer prognosis and therapy selection

How does Gene expression patterns act as biomarkers for cancer prognosis and treatment response.

Through transcriptional immune signature- pattern of gene expression that tells us what the immune system is doing.

If a tumor has high expression of genes associated with CD8 T cells, it may indicate that many cytotoxic T cells are present.

What are the 2 broad categories of Biomarkers

Prognostic: predict survival irrespective of treatment
Predictive: predict clinical outcome/survival on a specific treatment

Why are liquid biopsies better than solid biopsy

Minimally invasive

Easier to repeat.

Can monitor tumor changes over time.

May capture information from several tumor sites.

IFN-γ-associated chemokines help attract immune cells into tumors in the TME. Explain

Activated T cells

Produce IFN-γ

Stimulate chemokines such as CXCL9 and CXCL10

Recruit more T cells

Stronger antitumor response

Can higher tumour mutational burden be advantageous to the immune system?

Yes. Because more mutations equal to more abnormal protein synthesis leading to neoantigens. Which will be recognised as foreign by the T CELL

Mismatch repair-deficient tumors responded better to PD-1 blockade than mismatch repair-proficient tumors. Why?

Mismatch repair deficiency leads to mutational burden Because more mutations equal to more abnormal protein synthesis leading to neoantigens. Which will be recognised as foreign by the T cell

In immunotherapy sensitive tumours, will you choose a adjuvant therapy or neoadjuvant immunotherapy for a complete pathological response (no viable tumor cells are detected in the examined surgical specimen.)

Neoadjuvant

Tertiary lymphoid structures (TLS) in tumours is a predictive or prognostic marker

Prognostic

What Interferons support dendritic-cell activation and antigen presentation.

Type I interferons, especially IFN-α and IFN-β,

How type I interferon activates antitumor immunity/ Type I interferon signaling is required for efficient accumulation of cross-priming dendritic cells in tumors. Explain

Dying tumor cells release danger signals

Type I IFN production (IFN-α/β)

Activation of cross-presenting dendritic cells

Cross-priming of naive CD8 T cells

Activated CD8 T cells kill tumor cells

Define DAMP and PAMP. what is the function

PAMPs (pathogen-associated molecular patterns): Molecules associated with microorganisms, such as bacterial LPS or viral RNA.

DAMPs (damage-associated molecular patterns): Molecules released or exposed by stressed or damaged host cells, including tumor cells.

DAMPs and PAMPs activate innate immune sensors that can trigger type I IFN production.

STING pathway

STING stands for stimulator of interferon genes.

1. Tumor cells release DNA.

2. Dendritic cells detect tumor-derived DNA.

3. The STING pathway becomes activated.

4. Dendritic cells produce IFN-β and other inflammatory signals.

5. CD8 T-cell responses are stimulated.

Cytosolic dsDNA → cGAS → cGAMP → STING → TBK1 → IRF3 → IFN-I.

Functions of type 1 IFN

What is immunogenic cell death

Immunogenic cell death means dying tumor cells produce signals that activate the immune system. These signals help dendritic cells take up tumor antigens and mature. Mature dendritic cells can then activate tumor-specific T cells.

Molecules and functions in immunogenic cell death

Molecule	Function
Calreticulin	Exposed on the cell surface; promotes uptake by phagocytes
HMGB1	Released from dying cells; can activate innate immune receptors
ATP	Released as a danger signal; promotes immune-cell recruitment and activation

Integration of multiple parameters for the molecular profiling of cancer. Draw

Relationship of antibiotic and gut microbiome and immune response

Antibiotic-associated microbiome disruption:

• Reduced beneficial bacteria.

• Impaired immune stimulation.

• Weaker dendritic-cell and T-cell responses.

• Reduced tumor control.

Immune-supportive microbiome:

• Beneficial bacterial signals.

• Increased antigen-presenting-cell activation.

• Improved T-cell activity.

• Stronger antitumor immunity.

What are the 2 tools you use for immune profiling

Spatial transcriptomics and single cell RNA seq

Immune profiling will yield useful predictive immune signatures and biomarkers; the host-specific biomarkers should be integrated with cancer-specific biomarkers for therapy selection: personalized treatment! Defend this

1. 1)  Transcriptional signatures of chemokines, infiltrating T and B cells, the gut microbiome and type-I IFN response genes constitute prognostic biomarkers as well as predictive biomarkers for Immunotherapy and chemotherapy

2. 2)  A clinically favorable type-I IFN response signature is inititated by tumor-derived dsDNA and cyclic di-nucleotides triggering the STING DNA sensing pathway

3. 3)  Radiotherapy leads to triggering of the STING pathway and initiation of a type-I IFN response (+possibly other DAMPs and TLR triggering)

4. 4)  Chemotherapy can induce immunogenic cell death leading to the release of DAMPs (Calreticulin, HMGB1, ATP) that can trigger a.o. TLRs and induce DC/APC maturation and leverage T cell immunity

5. 5)  Accumulating immune monitoring evidence shows that conventional anti-cancer therapies depend on immune activation and an anti-tumor T cell response (IFN-I profiles and commensal bacterial strains!) for their efficacy