L7: Cancer Immunology

Learning objectives

• What is the cancer-immunity cycle?

• What is the relationship of dendritic cells, T cells, cancer cells, and tumor antigens?

• What are the different types of tumor antigens?

• What is immune therapy?

• What are immune checkpoints and the principles of immune checkpoint inhibitors

  in cancer treatment?

• What are the different types of cancer vaccines?

• What are the conjugated antibody-based immune therapies?

• What are the non-conjugated antibody-based immune therapies?

Cancer-immunity cycle

• release of cancer cell antigens (cancer cell death)

• cancer antigen presentation to DCs/APCs

• priming and activation of APCs and T cells

• traficking of T cells to tumours

• infiltration of T cells via stroma and into tumours

• recognition of cancer cells by T cells

• Killing of cancer cells

Tumour antigens

Tumour-associated antigens (TAAs)

Characteristics

• normal proteins or carbohydrates expressed in a abnormal way relative to its status in the healthy and fully differentiated state

Wrong concentration

• HER2

  • expressed at low levels by epithelial cells

  • over-expressed due to amplification of HER2 gene in breast cancer → uncontrolled proliferation

• CD20

  • surface marker that is expressed only at low levels on all normal B cells

  • over-expressed by malignant B cells

Wrong place

• cancer-testis antigen

  • normally expressed in spermatogonia and spermatocytes

  • found in cancer cells of other cell types

  • example: MAGE proteins in melanomas

• TRP-1

  • normally expressed in intracellular vescicles in normal cells

  • expressed in plasma membrane in melanoma cell

  • wrong subcellular locations

Wrong time

• embryonic antigens and proteins

• carcinoembryonic antigen (CEA)

  • normally expressed in fetal liver, intestines and pancreas

  • expressed in colon, breast and ovarian cancer

• alpha-feoprotein (AFP)

  • normally expressed in fetal liver

  • expressed in liver cancer

Tumour-specific antigens (TSAs)

• new macromolecules (present in tumour cells but not in normal cells)

• presented on MHCI

• ✔︎true immunogens → provoke immine response

• locate on tumour cell surface or its interior

• how are TSA be generated

  • chromosomal translocation fused DNA → forming new gene

  • abnormal carbohydrates / proteins produced by mutated gene

  • viral proteins expressed due to infection of oncogenic virus

  • non-mutated gene transcribed in abnormal way

    • alternative reading frame

    • opposite direction of transcription

    • pseudogene sequence

Evasion of immune response against tumours

• tumour rejection: regression of tumour induced by obvious immune response

• immunospressive cells

  • myeloid-derived suppressor cells (MDSCs)

  • Treg

  • tumour associated macrophages (TAMs)

• TGFß

  • block functions of T cells and NK cells

  • suppress antibody synthesis

• abnormal tumorous vasculature

  • capillaries supporting malignant cell growth: disorganised and lack integrins → hinder leukocyte extravasation

  • hypoxia → hinder leukocytes functions

Immune therapy

Antibody-based immunotherapies

Unconjugated mAbs therapy

• activate immune cells (esp in innate immunity)

• mAb binds to TAA or TSA on tumour cells → recognised by receptors on macrophages, neutrophils, eosinophils or NK cells

• tumour cell then destroyed by phagocytosis, ADCC or complement-meditaed lysis

  • reduce blood supply to malignant cells by interfering angiogenic factors

  • sequester growth factors for tumour expansion

Conjugated mAbs therapy

• Immunotoxin and antibody-drug conjugate (ADC)

  • mAbs specific for a TAA or TSA linking to a toxin or drug

    • e.g. Ricin A

  • toxin inhibits protein or nucleic acid synthesis/ damages DNA after internalised by tumour cells

• Antibody-directed enzyme/ pro-drug therapy (ADEPT)

  • mAb specific for a TTA or TSA conjugated to enzyme: converting pro-drug → active cytotoxic drug

  • e.g. alkaline phosphatase conjugated mAb

• Immunoradiaisotopes

  • mAb specific for a TAA or TSA conjugated to radioisotopes (I131 and Y90)

  • labelled mAb binds to tumour antigens and damage tumour cells

  • drawbacks: catabolised and accumulated in liver or kidney

• Immunocytokines

  • mAb specific for a TAA or TSA conjugated to cytokine: link tumour cell to an effector leukocytes with receptor for that cytokine

  • e.g. IL2 conjugated mAb → T cell action

Cancer vaccine

Pathogen-based

• target virous that causes cancer

• using harness fragments of pathogens or dead / weakened pathogens or toxins produced by pathogens

• examples

  • vaccine with proteins of HBV → reduce hepatitis and liver cancer

  • vaccine with proteins of HPV → reduce cervical cancer

TAA/ TSA-based

• TAA vaccine

  • might provoke attack against normal cells

  • ✔︎ TAA expressed in non-vital organs → not threaten survival of host

• TSA vaccine

  • involve distinctive peptides from oncogenic versions of the proteins

  • specifically taerting cancer cells

• require good prediction of mutataed antigens

• peptide vacines

  • enriched from tumour cells or by artificial synthesis

  • peptides recognised by APCs → presented to T cells → immune response

  • drawbacks: not all antigens are strongly immunogenic

Tumour cell-based vaccine

• from patients or from other patient with similar cancer

• genetically modified → produce TAAs → detected by APCs → immune response

DNA vaccine

• plasmid DNA containing genetic code for TSA or TAA + regulatory sequence

• expressed on cell surface and presented by APCs → T cell and immune response

Dendritic cell-based vaccine

• load DCs with TAA or TSA by electroporation or phagocytosis → presented TSA or TAA and adminitered back to patient

• require cytokine cocktail to turn precursor cell → mature DC

  • IL1ß, IL6, prostaglandin E2, monocyte-conditioned medium, TLR ligands

• optimal DC vaccine can

  • migrate to lymph nodes

  • present antigens and costimulate T cells

  • survive for optimal T cell activation

Adoptive T cell cancer therapy

CAR-T cell therapy

• T cells are genetically engineered → produce receptors on surface (CAR): specificity towards cancer cell surface proteins

• CAR structure

  • extracellular antigen recognition domain

  • intracellular TCR signalling domain

  • costimulatory domain

• anti-CD19 CAR-T

  • highly effective against refractory ALL, CLL and DBCL

  • require costimulatory motif module for proliferation and persistence

  • possible problems

    • hyperimmune activation → cytokine release syndrome

    • cross reaction → kill normal B cells

    • resistance due to CD19 loss

TCR therapy

• T cells are genetically engineered → produce specific TCR: recognise TAA or TSA presented by MHC on cancer cell

• drawbacks

  • cross reaction: lethal off target or off tissue killing

  • ineffective against solid tumours due to immunosupressive microenvironment, low efficacy and persistence

Immune checkpoints

Characteristics

• CTLA4

  • expressed on T cell surface 2 days after activation

  • compete with CS28 to B7 ligands on APCs → shit down TCR signalling and induce inhibitory signal for T cells

• PD1

  • programmed death → apoptosis

Principles of immune checkpoint inhibitors in cancer treatment

• block immune checkpoints on T cells → enhance T cell infiltration into tumour cells

• activated T cells → produce IFN-γ → PD-L1 expression