1. Tumor Immunology
Prof. Nattiya Hirankarn, MD, PhD
CU Cancer Immunotherapy Excellence Center
Faculty of Medicine, Chulalongkorn University

2. ILCs

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

6. 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

9. 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

10. Viral antigen & tumor
antigen
MHC class I present
peptide to CD8+ T
cells
MHC class II present
peptide to CD4+ T
cells

11. HLA class I
groove:close angle
shorter peptide (8-10aa)
HLA class II
groove: open angle
longer peptide (10-20aa)

13. Hallmarks of cancer: The next generation
Hanahan and Weinberg. Cell 2011

15. 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.

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

21. To eradicate cancer
• We must understand the fundamentals of tumor immunology
• Tumor antigens
• Immune evasion by tumors
• State-of-the-art cancer immunotherapy

22. Tumor antigens

23. Cancer origin
• DNA instability
• Accumulation of genetic alterations
• Oncogenes/tumor suppressor genes
• Random mutations
Roitt’s Essential Immunology

24. Tumor antigens
• Altered protein expression in/on cells:
• Mutation
• Overexpression
• Underexpression

25. Tumor Antigens
• Neoantigens
• Unmutated proteins, but abnormally expressed
• Oncogenic viral proteins
• Oncofetal antigens
• Altered glycolipid/glycoprotein antigens
• Others

26. 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

27. 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

28. Examples of tumor antigens
• Oncogenic viral proteins
• EBV: B cell lymphoma
• HPV: cervical cancer
• HBV/HCV: hepatocellular carcinoma (chronic inflammation)

29. 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

30. • The nature of the tumor antigens determines its immunogenicity.
Especially its foreignness from normal proteins.

31. Specificity of tumor antigens
Coulie PG et al. Nat Rev Canc. 2014
Highly immunogenic Less immunogenic

32. To eradicate cancer
• We must understand the fundamentals of tumor immunology
• Tumor antigens
• Immune evasion by tumors
• State-of-the-art cancer immunotherapy

33. Tumor escape mechanisms

34. Tumor escape mechanisms
• Reduced immunogenicity of tumors
• Inhibition of immune responses

35. 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

36. Vesely MD et al. Anuu Rev Immunol. 2011
Immune evasion mechanisms

37. To eradicate cancer
• We must understand the fundamentals of tumor immunology
• Tumor antigens
• Immune evasion by tumors
• State-of-the-art cancer immunotherapy

39. “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.”

40. 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.

41. 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

43. 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.

45. Upon activation, T cells
upregulate CTLA-4

51. 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.

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

59. 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

65. 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.

68. 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.

69. 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

72. 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.

74. Chemotherapy / Radiation to Improve
Immunotherapy
Chemotherapy and radiation therapy can enhance
anti-tumor immune responses.

75. 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.

76. A different perspective on chemotherapy

78. 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

80. 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

84. Thank you for your attention!