Tumor Immunology - Hyperexcision

Last updated: November 12, 2024

Using examples, enumerate the different classes of tumour antigens which are the targets of human immune response
- Products of passenger mutations (diverse mutated genes)
  - Products of passenger mutations (mutations which play no role in tumorigenesis). May stimulate an adaptive immune response.
- Products of driver mutations (oncogenes or mutated tumour suppressor genes)
  - Products of genes that are involved in tumorigenesis
    - Example: BRCA1, BRCA2 in breast cancer and Ovarian Cancer
- Aberrantly expressed proteins
  - Normal, unmutated proteins whose expression is dysregulated in the tumour. Their aberrant expression is enough to make them immunogenic.
  - Examples: CEA in colorectal adenocarcinoma
- Viral antigens
  - Antigens produced by tumours driven by oncogenic viruses
  - Example: HPV E6 and E7 in cervical carcinoma
- Oncofetal
  - Antigens expressed in fetal tissues and in cancerous somatic cells
  - Example: CEA in colorectal adenocarcinoma
- Oncoviral
  - Antigens encoded by oncogenic viruses
  - Example: HPV E6 and E7 in cervical carcinoma
- Mutated
  - Antigens expressed by cancer as a result of genetic mutation or alterations in transcription (amplification)
  - Example: BRCA1 and BRCA2 in breast and ovarian carcinoma
- Overexpressed/ accumulated
  - Antigens expressed by both normal and neoplastic tissue with the level of expression highly elevated in neoplasia
  - Example: HER2/Neu in breast cancer, BING-4 in melanoma
- Cancer-testis
  - Antigens expressed only by cancer cells and adult reproductive tissues such as testis and placenta
- Lineage-restricted
  - Antigens expressed largely by a single cancer histiotype
  - Example: PSA in prostate adenocarcinoma, Melan-A/MART-1 in melanoma
- Post-translationaly altered
  - Antigens whose altered glycosylation is tumour-associated
  - Example;: MUC1 in Ductal adenocarcinoma and Renal cell carcinoma
- Idiotypic
  - A specific “clonotype” of highly polymorphic genes expressed tumour cells
  - Example: Monoclonal kappa or lambda light chains in Multiple Myeloma, Monoclonal TCR in T cell lymphoma
Briefly describe the human immune response to tumours
- Macrophages
  - Cancer cells and stromal cells produce chemokines (CSF-1, CCL2, CCL3) → recruitment of monocytes and resident macrophages
  - M1 macrophage (anti-tumor)
    - Phagocytosis
    - Intracellular destruction of apoptotic cells and waste products)
    - Production of inflammatory cytokines
    - Antigen precentation via MHCII to CD4+ T-cells, and MHCI to CD8+ T-cells
  - M2 macrophage (Pro-tumor)
    - Anti-apoptotic, stimulates proliferation and inflammation (TNF and NF-KB signalling)
    - Angiogenesis (IL-17, IL-23, FGF, VEGF)
    - Suppression of immune response (TGF-B, IL-10)
- Dendritic Cells
  - Antigen presentation via MHCI to CD8+ T-cell and MHCII to CD4+ T-cell
  - Cytokine production and initiation of inflammation
- Natural Killer Cells
  - Cytotoxic activity (perforin and granzyme)
  - Activate macrophages (IFN-y)
  - Lyse MHC I negative tumor cells
- Cytotoxic T cells
  - Antigen recognition displayed on MHC I by TCR on CTLs
  - Cytotoxicity (Perforin, Granzyme)
  - Apoptosis (Fas ligand binding to FASDR CD95)
- Humoral immunity (B-cells and antibodies)
  - Alters function of antigenic targets on tumor cells
  - Opsonize tumor cellls for the presentation of tumor antigens by DCs
  - Antibody bound tumor cells activate complement cascade
  - Contribute to NK cell mediated tumor killing via antibody-dependent cell-mediated cytotoxicity
Describe 5 mechanisms of immune evasion by tumours
- Low antigenicity and or antigen loss by tumors
  - Elicit little inflammation and co-stimulation
  - Express few non-self antigens
  - Antigen loss variants – stop expressing antigens targeted by immune response
- Non-Expression of MHC 1 molecules
  - Evade CD8+ cytotoxic T cells
  - NK cells kill MHC I negative Tumors
- Production of immunosuppressive cytokines
  - Some tumors secrete TGF-B and IL-10
  - Some tumor induce Treg response
- Inhibition of T cell activation
  - Tumors express PD-1 and CTLA4
  - Tumors induce low levels of B7 costimulators on APCs
  - Net result is reduced T cell activation upon recognition of tumor antigens
- Induction of Treg activity
  - Treg activation suppresses antitumor immune response
- Rapid growth
  - Rapid growth of tumor outstrips the immune defense
Describe any 4 immunotherapeutic strategies against tumours
- Passive
  - Antibody therapy
    - Rituximab: targets CD20 on B-cell NHL, triggering Ab mediated cell cytotoxicity
    - Alemtuzumab: targets CD52 on CLL
    - Trastuzumab (Herceptin): Targets Her2/Neu in breast cancer
    - Cetuximab: Targets EGFR on stage IV colorectal cancer, Head and neck cancers
- Adaptive cellular therapy
  - CTLs isolated from blood or tumor infiltrates are expanded in vitro culture and reintroduced to destroy tumor cells
- Chimeric antigen receptors
  - Chimeric antigen receptors that recognize tumor antigens are genetically introduced in vitro and transferred back into the patient
- Active
  - Vaccination
    - HPV vaccine: Prevents cervical cancer
  - Checkpoint blockade
    - Antibodies that block CTLA4: Melanoma (2011)
    - Antibodies that block PD-1 or its ligan PD-1L: anti-PD1 (2014)
  - Cytokine therapy
    - IL-2
    - IFN-a
    - IFN-Y

Reference Intervals ›

Biochemistry

ACTH	P: <80 ng/L
ALT	P: 5–35 U/L
Albumin	P: 35–50 g/L
Aldosterone	P: 100–500 pmol/L
Alk. phosphatase	P: 30–130 U/L
α-Amylase	P: 0–180 IU/dL
α-Fetoprotein	S: <10 kU/L
Angiotensin II	P: 5–35 pmol/L
ADH	P: 0.9–4.6 pmol/L
AST	P: 5–35 U/L
Bicarbonate	P: 24–30 mmol/L
Bilirubin	P: 3–17 μmol/L
BNP	P: <50 ng/L
CRP	P: <10 mg/L
Calcitonin	P: <0.1 mcg/L
Calcium (ionized)	P: 1.0–1.25 mmol/L
Calcium (total)	P: 2.12–2.60 mmol/L
Chloride	P: 95–105 mmol/L
Cholesterol	P: <5.0 mmol/L
VLDL	P: 0.128–0.645 mmol/L
LDL	P: <2.0 mmol/L
HDL	P: 0.9–1.93 mmol/L
Cortisol AM	P: 450–700 nmol/L
Cortisol Midnight	P: 80–280 nmol/L
CK ♂	P: 25–195 U/L
CK ♀	P: 25–170 U/L
Creatinine	P: 70–100 μmol/L
Ferritin	P: 12–200 mcg/L
Folate	S: 2.1 mcg/L
FSH	P: 2–8 U/L ♂; >25 menopause
GGT ♂	P: 11–51 U/L
GGT ♀	P: 7–33 U/L
Glucose (fasting)	P: 3.5–5.5 mmol/L
Growth hormone	P: <20 mu/L
HbA1C (DCCT)	B: 4–6%
HbA1C (IFCC)	B: 20–42 mmol/mol
Iron ♂	S: 14–31 μmol/L
Iron ♀	S: 11–30 μmol/L
Lactate (venous)	P: 0.6–2.4 mmol/L
Lactate (arterial)	P: 0.6–1.8 mmol/L
LDH	P: 70–250 U/L
LH	P: 3–16 U/L
Magnesium	P: 0.75–1.05 mmol/L
Osmolality	P: 278–305 mosmol/kg
PTH	P: 0.8–8.5 pmol/L
Potassium	P: 3.5–5.3 mmol/L
Prolactin ♂	P: <450 U/L
Prolactin ♀	P: <600 U/L
PSA	P: 0–4 mcg/mL
Protein (total)	P: 60–80 g/L
Red cell folate	B: 0.36–1.44 μmol/L
Renin (erect)	P: 2.8–4.5 pmol/mL/h
Renin (recumbent)	P: 1.1–2.7 pmol/mL/h
Sodium	P: 135–145 mmol/L
TBG	P: 7–17 mg/L
TSH	P: 0.5–4.2 mU/L
T4	P: 70–140 nmol/L
Free T4	P: 9–22 pmol/L
TIBC	S: 54–75 μmol/L
Triglycerides	P: 0.50–2.3 mmol/L
T3	P: 1.2–3.0 nmol/L
Troponin T	P: <0.1 mcg/L
Urate ♂	P: 210–480 μmol/L
Urate ♀	P: 150–390 μmol/L
Urea	P: 2.5–6.7 mmol/L
Vitamin B12	S: 0.13–0.68 nmol/L
Vitamin D	S: 50 nmol/L

Arterial Blood Gases

pH	7.35–7.45
PaCO₂	4.7–6.0 kPa
PaO₂	>10.6 kPa
Base excess	±2 mmol/L

Urine

Cortisol (free)	<280 nmol/24h
Hydroxyindole acetic acid	16–73 μmol/24h
Hydroxymethylmandelic acid	16–48 μmol/24h
Metanephrines	0.03–0.69 μmol/mmol cr.
Osmolality	350–1000 mosmol/kg
17-Oxogenic steroids ♂	28–30 μmol/24h
17-Oxogenic steroids ♀	21–66 μmol/24h
17-Oxosteroids ♂	17–76 μmol/24h
17-Oxosteroids ♀	14–59 μmol/24h
Phosphate (inorganic)	15–50 mmol/24h
Potassium	14–120 mmol/24h
Protein	<150 mg/24h
Protein/creatinine ratio	<3 mg/mmol
Sodium	100–250 mmol/24h

Haematology

WCC	4.0–11.0 ×10⁹/L
RBC ♂	4.5–6.5 ×10¹²/L
RBC ♀	3.9–5.6 ×10¹²/L
Hb ♂	130–180 g/L
Hb ♀	115–160 g/L
PCV ♂	0.4–0.54 L/L
PCV ♀	0.37–0.47 L/L
MCV	76–96 fL
MCH	27–32 pg
MCHC	300–360 g/L
RDW	11.6–14.6%
Neutrophils	2.0–7.5 ×10⁹/L (40–75%)
Lymphocytes	1.0–4.5 ×10⁹/L (20–45%)
Eosinophils	0.04–0.44 ×10⁹/L (1–6%)
Basophils	0–0.10 ×10⁹/L (0–1%)
Monocytes	0.2–0.8 ×10⁹/L (2–10%)
Platelets	150–400 ×10⁹/L
Reticulocytes	0.8–2.0% / 25–100 ×10⁹/L
Prothrombin time	10–14 s
APTT	35–45 s

Paediatric

Pulse Rate (bpm)
Neonate	140–160
Infant <1yr	120–140
1–5 years	110–130
5–12 years	80–120
>12 years	70–100
Respiratory Rate (tachypnoea)
0–2 months	≥60/min
2–12 months	≥50/min
1–5 years	≥40/min
>5 years	≥30/min
Blood Pressure (mmHg)
Term	65/45
1 year	75/50
4 years	85/60
8 years	95/65
10 years	100/70
Weight Formulas
3–12 months	(a + 9)/2 kg
1–6 years	2a + 8 kg
>6 years	(7a − 5)/2 kg
Haemoglobin (g/dL)
Term newborn	13–20
1 month	11–18
2 months	10–15
1–2 years	10–13
>2 years	11–14
MUAC (6 months–5 years)
Obese	>17.5 cm
Normal	13.5–17.4 cm
At risk	12.5–13.4 cm
Moderate malnutrition	11.5–12.4 cm
Severe malnutrition	<11.5 cm
Developmental Milestones
Social smile	1.5 months
Head control	4 months
Sits unsupported	7 months
Crawls	10 months
Stands unsupported	10–12 months
Walks	12–13 months
Talks	18 months
CSF WBC (/mm³)
Term newborn	0–25
>2 weeks	0–5

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