Cancer and the immune system

What is cancer?

What is the immune response to cancer?

Prospects for immune therapies

Cancer cells are out of control!

Usually derived from a single cell, forminga tumor

Benign tumors are noninvasive; malignanttumors can invade and spread

Cancers are classified according to their origin

Blood cell cancers: leukemias and lymphomas

How do cells become “transformed” intomalignant cells?

RadiationCarcinogensViruses

expression of oncogenes (aberrant versionsof proto-oncogenes

Types of regulatory genes

Proto-oncogenes- induce proliferation (invarious ways)

Tumor suppressors- inhibit cell proliferation

Regulators of apoptosis

Defects in any of these can lead to uncontrolledcell growth

p. 502

Mutations accumulate in these cells as theyare gradually converted to malignantcells

Translocations are associated with certainspecific tumors

p. 503

Immune system tumors

Solid or systemic?Acute or chronic?Immature or mature cells?Myelogenous or lymphocytic?

Tumor-specific antigensfound only on tumors

Tumor-associated antigens- may be gene products that normally are not expressed(or at abnormal levels)

Can these be isolated and used as vaccines?Diagnosis?Therapy?

p. 508

Most tumor antigens are NOT unique to tumors

Often these are fetal proteins (growth factorreceptors, e.g.)

CEA- carcinoembryonic antigen

AFP- alpha-fetoprotein

Immune response to tumors (after all, it’saltered self)

Probably cell-mediated response

Many tumors reduce MHC Class I expression

NK cells can kill these

Also macrophages add NK cells can attackantibody-coated tumor cells (ADCC)

Immune surveillance?

im

Tumors can evade immune response

Antitumor antibody can block T cell responses

Tumors can modulate antigens

Tumors can reduce MHC Class I expression

Tumors can reduce “second signal” expression

Strategies for immunotherapy

Make cells more immunogenicbetter CTL activation“vaccine” cells?

“reconstitution” of a second signal (p. 515)

Cytokine therapy

Many have been tried: (thanks to recombinantDNA technology

Problems:complexity of cytokine interactionshard to administerserious side effects

LAK cells (lymphokine-activated killers)grow blood cells in high levels of IL-2produce mostly NK cells (NOT tumor-specific)

TILs tumor-infiltrating lymphocytesmay have more tumor-specific activityand need less IL-2

Monoclonal antibodies

Idiotype-specific

Humanized

Heteroconjugates

Monoclonal antibody production, p. 519

p. 519

Cancer vaccines?

Antigenic peptides (tumor-specific and immunogenic

Delivery (recombinant vaccines)

Will they be effectively presented to T cells?

Some viral vaccines (e.g., against HPV)may be helpful

There is much to be done.