Tumor Immunology

Prof. Nattiya Hirankarn, MD, PhD

CU Cancer Immunotherapy Excellence Center

Faculty of Medicine, Chulalongkorn University

ILCs

NKG2D is an activating receptor on NK cells that recognize stress signal e.g., MICS

First Step of Innate Immune Cells to trigger specific T cell response • 1. Recognize danger signal (PAMP & DAMP) by pattern recognition

receptor (PRR) on the cells surface of • Macrophage

• Neutrophils

• Dendritic cells

• Epithelial cells

• These cells form the barrier interface between the body and the external environment

Dendritic Cells and macrophage act as APC, process and present Ag to T lymphocytes

DC is the most efficient APC to stimulate Naïve T cells. They have high level of co-stimulatory signals and express CCR7 to target to LN.

Draining LN and Spleen

Viral antigen & tumor antigen

MHC class I present

peptide to CD8+ T

cells

MHC class II present

peptide to CD4+ T

cells

HLA class I

groove:close angle

shorter peptide (8-10aa)

HLA class II

groove: open angle

longer peptide (10-20aa)

Hallmarks of cancer: The next generation

Hanahan and Weinberg. Cell 2011

Cancer immunoediting: TME

The tumor microenvironment (TME): tumor infiltrating lymphocytes and myeloid cells.

Intricate interplay among tumor cells, immune cells and inflammation gradually generates a pro-angiogenic and immunosuppressive environment (TME).

Inflammation plays a large role in manifesting the TME.

We do not yet fully understand how inflammation is caused: innate immune system?

Inflammation and cancer: viruses, carcinogens. Intrinsic- oncogenes; extrinsic TLR.

But, we are learning and are now developing a new generation of therapies that helps stimulate the immune system BACK into attacking tumors.

Cancer immunoediting : elimination, equilibrium and escape.

Elimination: immunosurveillance and removal of tumor cell.

Equilibrium: failure to eliminate leads to equilibrium and inflammation-TME. Escape: Inflammation attracts myeloid-derived suppressor cells (MDSC’s) and TAMs.

Inflammation causes immunosuppression and promotes metastasis.

(e.g. IL-10, TGF-b)

To eradicate cancer

• We must understand the fundamentals of tumor immunology

• Tumor antigens

• Immune evasion by tumors

• State-of-the-art cancer immunotherapy

Tumor antigens

Cancer origin

• DNA instability

• Accumulation of genetic alterations • Oncogenes/tumor suppressor genes • Random mutations

Roitt’s Essential Immunology

Tumor antigens

• Altered protein expression in/on cells: • Mutation • Overexpression • Underexpression

Tumor Antigens

• Neoantigens

• Unmutated proteins, but abnormally expressed

• Oncogenic viral proteins

• Oncofetal antigens

• Altered glycolipid/glycoprotein antigens

• Others

Examples of tumor antigens

• Neoantigens- • products of randomly mutated genes

• products of mutated oncogenes/tumor suppressor genes; highly immunogenic • Eg. p53 loss-of-function; fails to arrest cell division in cells that have damaged

DNA

Abbas Cellular and Molecular Immunology. 9th ed. 2018

Examples of tumor antigens

• Unmutated proteins, but abnormally expressed • (silence in normal cells, expressed in tumor cells)

• (made by normal cells, but tumor cells express excessive amounts)

• Breast: HER2/Neu

• Cancer-testis antigens: MAGE-1 in melanoma

Abbas Cellular and Molecular Immunology. 9th ed. 2018

Examples of tumor antigens

• Oncogenic viral proteins • EBV: B cell lymphoma

• HPV: cervical cancer

• HBV/HCV: hepatocellular carcinoma (chronic inflammation)

Examples of tumor antigens

• Oncofetal antigens • High expression in cancer and fetal tissues, not on adult tissues

• Increased expression in some inflammatory conditions

• a-fetoprotein (AFP) in hepatocellular carcinoma, gastric, pancreatic cancers

• carcinoembryonic antigen (CEA) in many tumors

• Altered glycolipid/glycoprotein antigens • MUC-1: breast cancer

• Others • Danger signals

• CD44-metastatic molecule

• The nature of the tumor antigens determines its immunogenicity.

Especially its foreignness from normal proteins.

Specificity of tumor antigens

Coulie PG et al. Nat Rev Canc. 2014

Highly immunogenic Less immunogenic

To eradicate cancer

• We must understand the fundamentals of tumor immunology

• Tumor antigens

• Immune evasion by tumors

• State-of-the-art cancer immunotherapy

Tumor escape mechanisms

Tumor escape mechanisms

• Reduced immunogenicity of tumors

• Inhibition of immune responses

Understanding Tumor immunology

• Clinically detected cancer • Tumor has evaded anti-tumor immune responses

• Cancer cells are derived from “previously normal” host cells • Low immunogenic cells

• Some cells present “tumor antigens” that are expressed by self tissues • leading to immunologic tolerance for the highest-avidity interaction

between MHC-peptide-TCR.

• Tumor microenvironment • Immunosuppressive

Vesely MD et al. Anuu Rev Immunol. 2011

Immune evasion mechanisms

To eradicate cancer

• We must understand the fundamentals of tumor immunology

• Tumor antigens

• Immune evasion by tumors

• State-of-the-art cancer immunotherapy

“By treating the patient, not the tumor, these therapies

hold the potential for safer and more durable control of cancer. In

fact, many believe that it is reasonable to start using that other “c”

word—cure—to describe the long-lasting responses we are seeing.”

William B. Coley, M.D. “Father of Cancer Immunotherapy” In the early 1890s,“Coley’s toxins (from Bacteria)” were used to treat over 1,000 cancer patients with these toxins, with varied success.

Nauts founded the Cancer Research Institute in 1953, which ever since has funded the work of scientists studying the link between cancer and the immune system.

The first modern non-specific cancer immunotherapy was Bacillus Calmette-Guérin (BCG). In 1990, BCG was approved by the FDA as first-line treatment for early forms of bladder cancer, for which it is still used as a mainstay of therapy.

They discovered that the cell lines that most readily took up BCG contained one of several cancer-causing mutations, including mutations in PTEN, known to be involved in the onset of bladder cancer. The cell lines resistant to BCG did not have these particular mutations

Huang G et al., Biol Chem. 2012

T cell Checkpoint Modulation

To exist, tumors must evolve

mechanisms to locally disable and/or

evade the immune system.

The goal of T cell checkpoint blockade is

to make T cell “off-switches” inaccessible

to tumor cells, thus restoring tumor-

specific immunity.

Upon activation, T cells

upregulate CTLA-4

Therapeutic Cancer Vaccines

To exist, tumors must evolve

mechanisms to locally disable and/or

evade the immune system.

The goal of therapeutic cancer

vaccination is to increase the

frequency of tumor-specific T cells.

Cancer Neoantigens Vaccine

Neoantigens are markers present on the surface of cancer cells but absent on normal tissue, making them attractive drug target candidates

Of six vaccinated patients, four had no recurrence at

25 months after vaccination, while two with recurrent

disease were subsequently treated with anti-PD-1

(anti-programmed cell death-1) therapy and

experienced complete tumour regression, with

expansion of the repertoire of neoantigen-specific T

cells.

1 3 j u ly 2 0 1 7 | VO L 5 4 7 | N AT U R E | 2 1 7

T cell Adoptive Transfer

To exist, tumors must evolve

mechanisms to locally disable and/or

evade the immune system.

The goal of T cell adoptive transfer is to

win the numbers game and overwhelm

the tumor with tumor-specific T cells

CAR therapy: chimeric antigen receptor

CAR- T cells: autologous T cells genetically modified to express chimeric antigen receptors.

Improving CAR-T cell immunotherapy.

Good for haematological malignancies; acute lymphoblastic leukemia

(ALL)- 90% clinical responses. B cell/CD19.

81 planned or active clinical trials ongoing against blood cancers

51 against solid tumors: problem is that CAR-T cells don’t work well

against solid tumors; just target surface peptides.

T-cell receptor therapy (TCR): Take T cells from a healthy doner. The variable region of each TCR chain has three hyper-variable complementarity determining

regions, or CDRs. This technology modifies these CDRs in order to enhance affinity to the cancer cell’s HLA peptide complex.

TCR therapy can target intracellular proteins in cancer cells.

Antibody-Drug Conjugates

The goal of effector antibodies is to

specifically target and kill tumors cells

using mechanisms which are difficult

to evade of suppress

Anti-inflammatory antibodies and agents:

Inflammation can drive cancer progression.

Agents that treat inflammation can help fight cancer.

Non-steroidal inflammatory drugs (NAIDs).

Anti-IL1β, anti-TNFα, anti-IL6.

Inhibit signaling pathways that trigger cytokine production

NF-ĸB, STAT3, HIF-1.

Chemotherapy / Radiation to Improve

Immunotherapy

Chemotherapy and radiation therapy can enhance

anti-tumor immune responses.

A different perspective on chemotherapy:

Immunogenic versus non-immunogenic cell death

Derer A, Deloch L, Rubner Y, Fietkau R, Frey B and Gaipl US (2015) Front. Immunol. 6:505.

A different perspective on chemotherapy

DNA Damage

cGAS

STING ER

Nucleosome release

CDN’s/DNA

cytokine production Inflammasome processing

‘Intrinsic‘ STING activation

CD8α

Dendritic cell

Cancer cell

T-cell Priming

Find Me, Eat Me Signals Chemokines

Type I Interferon

Attract antigen presenting cell

Phagocytose/ engulf

Lysosomal compartment Containing engulfed dead cell

DNA and proteins

ER

Type I IFN

Necrosis/Apoptosis

Cross presentation

MHC1

antigen

Cytotoxic T CELL

Target Tumor cells

Necrosis/Apoptosis

Extrinsic STING signaling

Autocrine/paracrine stimulation of DC’s by type I IFN

Virus infection

Chen DS & Mellman I. Immunity. 2013

The Cancer-immunity cycle

• Promote immunity

• Keep process in check, reduce immune activity

• Intratumoral Tregs • Macrophages • Myeloid-derived

suppressor cells

Thank you for your attention!