Day 10 · Cancer Immunology and Neuroimmunology

Max Krummel

Max Krummel is a Professor of Immunology at the University of California, San Francisco. His research focuses on understanding how the immune system works, aiming to develop new treatments for diseases like cancer. He is a pioneer in the field of immunotherapy, leveraging the body’s own immune system to combat diseases. Krummel’s lab employs cutting-edge techniques such as real-time imaging to study immune cells in action. Additionally, he is the co-founder of Foundery Innovations, a biotechnology company dedicated to developing new drugs based on his research.

Question - Answers:

What was the rationale for looking into CTLA-4 at that point in time?
- Before the genome was published, research primarily involved injecting animals with antibodies.
- CTLA-4’s inhibitory role in T-cell activation: It’s now understood that CTLA-4 acts as a “brake” on the immune system, preventing overactive T-cell responses. Scientists in the 1950s, amid growing understanding of T-cell regulation, were likely interested in mechanisms controlling immune responses.
- Potential links to transplantation and autoimmunity: Early studies hinted at CTLA-4’s involvement in transplantation and autoimmunity. These areas were actively investigated in the 1950s, making CTLA-4 potentially relevant.
How does tumor burden impact the efficacy of anti-CTLA-4 therapy?
- Tumor burden’s impact is related to the chaos and mutation rate of the tumor, possibly following a non-linear function.
- Reduced Response: Larger tumors generally exhibit a lower response rate to anti-CTLA-4 therapy compared to smaller tumors.
- Immune Suppression: Large tumors create a more immunosuppressive environment, making it harder for anti-CTLA-4 therapy to activate the immune system effectively.
- Reduced Immune Cell Infiltration: Large tumors often have reduced immune cell infiltration, crucial for anti-CTLA-4 therapy.
- Increased Immunosuppressive Cells: Large tumors tend to harbor more immunosuppressive cells and molecules that hamper anti-CTLA-4 therapy’s efficacy.
The study focused on disabling inhibitory checkpoints of T cells. Alternatively, is there a way to boost activity or costimulation signals coming from APCs in the tumor microenvironment to suppress it?
- Targeting costimulatory molecules directly: Using antibodies or other agents to activate costimulatory molecules on APCs like CD40, OX40, or ICOS.
- Inhibiting negative regulators of APC function: Blocking molecules that suppress APC activity, such as PD-L1 or IDO.
- Enhancing antigen presentation: Increasing MHC molecule expression on APCs or improving tumor antigen processing and presentation.
- Modulating the tumor microenvironment: Targeting factors in the tumor microenvironment suppressing APC function, like TGF-beta or regulatory T cells.
If you treat a mouse with antibiotics and deplete the gut microbiome, are there differences in the ability to respond to checkpoint inhibitor therapy? Does it vary with cancer that arises in different tissues?
- Gut Microbiome’s Role: The gut microbiome crucially modulates the immune system’s response to cancer therapies.
- Antibiotics’ Impact: Antibiotics can disrupt the gut microbiome, potentially hindering checkpoint inhibitor effectiveness.
- Tissue-Specific Effects: Ongoing research explores tissue-specific differences. Some studies suggest potential variations in how the gut microbiome influences checkpoint inhibitor response in different cancer types.

How Drosophila can be used to study neuroinflammatory disorder

Prof. Sveta Chakarabarti, IISc

Neuroinflammation:

Many classical receptors are expressed by neurons.
Inflammation can have both positive and negative impacts.
- Injury: Removal of dead cells is essential.
Primary neuronal cells from rats were taken, a cleavage cascade was initiated, and Abeta cell treatment was administered. They observed activation of NF-Kappa-beta (immune response) in neuronal cells.

Model Systems:

Genetic modifications in mouse models affect AD molecules with detrimental effects.
Genes implicated in human disease:
- 77% are homologous to Drosophila.
- 65% are homologous to nematodes.
Yeast: Large-scale molecular screens.
Drosophila: Quick genetics/ extensive toolbox to manipulate genes.
C. elegans: Quick genetics/ extensive toolbox to manipulate genes.
Mouse: Mammalian genetic model/ closer model to humans.
Diseases studied include: Diabetes, mental retardation, epilepsy, infection (innate immunity), neurodegenerative diseases, muscular dystrophy.

Models for Innate Immune System:

Only innate immunity.
Innate immunity conserved among Drosophila and mammals.
Live in a microbe-enriched environment.
Toll receptors: Discovered in 1985 during Drosophila embryology.
1996: Required for innate immunity.
1997: Toll-like genes in mammals.

Characteristics of the immune system:

Vertebrates and invertebrates.
First line of defense.
Rapid.
Nonspecific.
Barriers → recognition → remove and destroy → distinguish self and non-self → memory? (trained immunity).
- Giving a heat-killed pathogen provides protection upon subsequent exposure.

Two ways to produce an animal model of a human genetic disease:

By loss of function of the gene homologous to the human gene mutated in the disease.
- Recessive genetic diseases due to loss of function mutation require that the animal model has the homologous gene affected in the disease.
  - Example: Fragile X syndrome.
By expressing or overexpressing the human mutant protein in the animal.
- Dominant genetic disease due to a gain of function mutation.
- Inducible expression in Drosophila using the UAS/Gal4 system.

Identifying the suppressor genes of these human diseases in Drosophila by a genetic approach:

To understand molecular mechanisms of disease.
Mutagenesis and collection of mutants.