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Fig. 9.14 Mechanisms by which microbes may promote autoimmunity. A, Normally, an encounter of

mature T cells with self antigens presented by resting tissue antigen-presenting cells (APCs) results in peripheral tolerance. B, Microbes may activate the APCs to express costimulators, and when these APCs present

self antigens, the specific T cells are activated, rather than being rendered tolerant. C, Some microbial antigens may cross-react with self antigens (mimicry). Therefore, immune responses initiated by the microbes

may become directed at self cells and self tissues. This figure illustrates concepts as they apply to T cells;

molecular mimicry also may apply to self-reactive B lymphocytes.

194 CHAPTER 9 Immunologic Tolerance and Autoimmunity

periodontal bacterial infections are associated with

rheumatoid arthritis. It is postulated that the inflammatory responses to these bacteria lead to enzymatic

conversion of arginines to citrullines in self proteins,

and the citrullinated proteins are recognized as nonself and elicit adaptive immune responses.

• Infections also may injure tissues and release antigens that normally are sequestered from the immune

system. For example, some sequestered antigens

(e.g., in testis and eye) normally are not seen by the

immune system and are ignored. Release of these

antigens (e.g., by trauma or infection) may initiate an

autoimmune reaction against the tissue.

• The abundance and composition of normal commensal

microbes in the gut, skin, and other sites (the microbiome) may also influence the health of the immune

system and the maintenance of self-tolerance. This possibility has generated a great deal of interest, but normal variations in the microbiome of humans related to

environmental exposure and diet make it difficult to

define the relationship between particular microbes and

the development of autoimmune diseases.

Paradoxically, some infections appear to confer protection from autoimmune diseases. This conclusion is

based on epidemiologic data and limited experimental

studies. The basis of this protective effect of infections

is unknown.

Several other environmental and host factors may

contribute to autoimmunity. Many autoimmune diseases are more common in women than in men, but

how gender might affect immunologic tolerance or

lymphocyte activation remains unknown. Exposure

to sunlight is a trigger for the development of the

autoimmune disease SLE, in which autoantibodies are

produced against self nucleic acids and self nucleoproteins. It is postulated that these nuclear antigens may

be released from cells that die by apoptosis as a consequence of exposure to ultraviolet radiation in sunlight.

SUMMARY

• Immunologic tolerance is specific unresponsiveness

to an antigen induced by exposure of lymphocytes

to that antigen. All individuals are tolerant of (unresponsive to) their own (self) antigens. Tolerance

against antigens may be induced by administering

that antigen in particular ways, and this strategy may

be useful for treating immunologic diseases and for

preventing the rejection of transplants.

• Central tolerance is induced in immature lymphocytes that encounter antigens in the generative lymphoid organs. Peripheral tolerance results from the

recognition of antigens by mature lymphocytes in

peripheral tissues.

• Central tolerance of T cells is the result of strong recognition of antigens in the thymus due to an abundance

of antigen or a high affinity of TCRs. Some of these

self-reactive T cells die (negative selection), thus eliminating the potentially most dangerous T cells, which

express high-affinity receptors for self antigens. Other

T cells of the CD4 lineage develop into regulatory T

cells that suppress self-reactivity in the periphery.

• Peripheral tolerance in T cells is induced by multiple mechanisms. Anergy (functional inactivation)

results from the recognition of antigens without

costimulators (second signals). The mechanisms of

anergy include a block in TCR signaling and engagement of inhibitory receptors such as CTLA-4 and

PD-1. Self-reactive regulatory T cells suppress potentially pathogenic T cells. Deletion (death by apoptosis) may occur when T cells encounter self antigens.

• In B lymphocytes, central tolerance occurs when

immature cells recognize self antigens in the bone

marrow. Some of the cells change their receptors

(receptor editing), and others die by apoptosis (negative selection, or deletion). Peripheral tolerance is

induced when mature B cells recognize self antigens

without T cell help, which results in anergy and death

of the B cells, or engagement of inhibitory receptors.

• Autoimmune diseases result from a failure of selftolerance. Multiple factors contribute to autoimmunity, including the inheritance of susceptibility genes

and environmental triggers such as infections.

• Many genes contribute to the development of autoimmunity. The strongest associations are between

HLA genes and various T cell–dependent autoimmune diseases.

• Infections predispose to autoimmunity by causing inflammation and stimulating the expression of

costimulators or because of cross-reactions between

microbial and self antigens.

CHAPTER 9 Immunologic Tolerance and Autoimmunity 195

REVIEW QUESTIONS

1. What is immunologic tolerance? Why is it important?

2. How is central tolerance induced in T lymphocytes

and B lymphocytes?

3. Where do regulatory T cells develop, and how do

they protect against autoimmunity?

4. How is functional anergy induced in T cells? How

may this mechanism of tolerance fail to give rise to

autoimmune disorders?

5. What are the mechanisms that prevent immune

responses against commensal microbes and fetuses?

6. What are some of the genes that contribute to autoimmunity? How may MHC genes

play a role in the development of autoimmune

diseases?

7. What are some possible mechanisms by which

infections promote the development of autoimmunity?

Answers to and discussion of the Review Questions are

available at Student Consult.

196

Immune Responses to Cancer

Cells and Normal Foreign Cells

10

Cancer and organ transplantation are two situations in

which the immune response to human cells that are genetically distinct from the normal self has important clinical

consequences. In order for cancers to grow, they have to

evade host immunity, and effective methods of enhancing

patients’ immune responses against tumors, called cancer

immunotherapy, have transformed clinical oncology. In

organ transplantation, the situation is the reverse: immune

responses against grafted tissues from other people are a

major barrier to successful transplantation, and suppressing

these responses is a central focus of transplantation medicine. Because of the importance of the immune system in

host responses to tumors and transplants, tumor immunology and transplantation immunology have become subspecialties in which researchers and clinicians come together

to address both fundamental and clinical questions.

Immune responses against tumors and transplants

share several characteristics. These are situations in which

the immune system is not responding to microbes, as it

usually does, but to noninfectious cells that are perceived as

foreign. The antigens that mark tumors and transplants as

foreign may be expressed in virtually any cell type that is the

target of malignant transformation or is grafted from one

individual to another. Therefore, immune responses against

tumors and transplants may be directed against diverse cell

types. Also, the immune system uses the same major mechanism, the activation of cytotoxic T lymphocytes (CTLs), to

kill both tumor cells and the cells of tissue transplants.

In this chapter we focus on the following questions:

• What are the antigens in tumors and tissue transplants

that are recognized as foreign by the immune system?

• How does the immune system recognize and react to

tumors and transplants?

• How can immune responses to tumors and grafts be

manipulated to enhance tumor rejection and inhibit

graft rejection?

We discuss tumor immunity first and then transplantation, and we point out the principles common to both.

Immunology of Tumors

and Transplantation

CHAPTER OUTLINE

Immune Responses Against Tumors, 197

Tumor Antigens, 197

Immune Mechanisms of Tumor Rejection, 199

Evasion of Immune Responses by Tumors, 200

Cancer Immunotherapy, 202

Passive Immunotherapy With Monoclonal

Antibodies, 202

Adoptive T Cell Therapy, 203

Immune Checkpoint Blockade, 204

Stimulation of Host Antitumor Immune Responses

by Vaccination With Tumor Antigens, 206

Immune Responses Against Transplants, 207

Transplantation Antigens, 208

Induction of Immune Responses Against

Transplants, 208

Immune Mechanisms of Graft Rejection, 211

Prevention and Treatment of Graft Rejection, 212

Transplantation of Blood Cells and Hematopoietic

Stem Cells, 215

Summary, 216

CHAPTER 10 Immunology of Tumors and Transplantation 197

IMMUNE RESPONSES AGAINST TUMORS

For over a century scientists have proposed that a physiologic function of the adaptive immune system is to prevent the outgrowth of transformed cells and to destroy

these cells before they become harmful tumors. Control

and elimination of malignant cells by the immune system is called tumor immune surveillance. Several lines

of evidence support the idea that immune surveillance

against tumors is important for preventing tumor growth

(Fig. 10.1). However, the fact that common malignant

tumors develop in immunocompetent individuals indicates that tumor immunity is often incapable of preventing tumor growth or is easily overwhelmed by rapidly

growing tumors. Furthermore, biologists now consider

the ability to evade immune destruction as a fundamental feature (“hallmark”) of cancers. This has led to the

growing realization that the immune response to tumors

is often dominated by tolerance or regulation, not by

effective immunity. The field of tumor immunology has

focused on defining the types of tumor antigens against

which the immune system reacts, understanding the

nature of the immune responses to tumors and mechanisms by which tumors evade them, and developing

strategies for maximally enhancing antitumor immunity.

Tumor Antigens

Malignant tumors express various types of molecules that may be recognized by the immune system

as foreign antigens (Fig. 10.2). Protein antigens that

elicit CTL responses are the most relevant for protective

antitumor immunity. These tumor antigens have to be

present in the cytosol of tumor cells in order to be recognized by CD8+ CTLs. The tumor antigens that elicit

immune responses can be classified into several groups:

• Neoantigens encoded by randomly mutated genes.

Recent sequencing of tumor genomes has revealed

that common human tumors harbor a large number of

mutations in diverse genes, reflecting the genetic instability of malignant cells. These mutations usually play

no role in tumorigenesis and are called passenger mutations. Many of these mutations result in expression of

mutated proteins, called neoantigens because they are

newly expressed in the tumor cells but not in the normal

cells of origin of the tumor. Because T cells only recognize peptides bound to major histocompatibility complex (MHC) molecules, mutated tumor proteins can be

recognized only if peptides carrying the mutated amino

acid sequences can bind to the patients’ MHC alleles.

Tumor neoantigens may not induce tolerance beca

CHAPTER 10 Immunology of Tumors and Transplantation

Types of Tumor Antigens Examples

Neoantigens

generated by

mutations unrelated

to tumorigenesis

Normal proteins

expressed

by tissue of

tumor origin

Abberrantly

expressed

normal proteins

Amplified genes/

overexpressed

normal proteins

Protein antigens

expressed by an

oncogenic virus

Random

passenger

mutations in

common cancers

Tyrosinase in

melanomas;

CD20 on

B cell lymphomas

Cancer testis

antigens in

many tumors

HER2/neu in

breast cancers

EBV nuclear

antigens in

EBV+ lymphomas

Demethylated gene

Viral gene

Oncogenic virus

Mutation

Fig. 10.2 Types of tumor antigens recognized by T cells. Tumor antigens that are recognized by tumorspecific CD8+ T cells may be mutated forms of various self-proteins that do not contribute to malignant

behavior of the tumor; products of oncogenes or tumor suppressor genes; self-proteins whose expression is

increased in tumor cells; and products of oncogenic viruses. Cancer/testis antigens are proteins that are normally expressed in the testis and are also expressed in some tumors. Tumor antigens also may be recognized

by CD4+ T cells, but less is known about the role that CD4+ T cells play in tumor immunity. EBV, Epstein-Barr

virus.

CHAPTER 10 Immunology of Tumors and Transplantation 199

they are not present in normal cells, and are the most

common targets of tumor-specific adaptive immune

responses. In fact, the number of these mutations in

human cancers correlates with the strength of the

antitumor immune responses patients mount and the

effectiveness of immunotherapies that enhance those

responses. In experimental tumors induced by chemical carcinogens or radiation, the tumor antigens are also

mainly random mutants of normal cellular proteins.

• Products of oncogenes or mutated tumor suppressor

genes. Some tumor antigens are products of mutations,

called driver mutations, in genes that are involved in the

process of malignant transformation. The driver mutations that encode tumor antigens may be amino acid

substitutions, deletions, or new sequences generated by

gene translocations, all of which can be seen as foreign.

• Aberrantly or overexpressed expressed structurally

normal proteins. In several human tumors, antigens

that elicit immune responses are normal (unmutated)

proteins whose expression is dysregulated in the tumors,

sometimes as a consequence of epigenetic changes such

as demethylation of the promoters in genes encoding

these proteins, and sometimes by gene amplification.

These structurally normal self antigens would not be

expected to elicit immune responses, but their aberrant expression may be enough to make them immunogenic. For example, self proteins that are expressed

only in embryonic tissues may not induce tolerance in

adults, and the same proteins expressed in tumors may

be recognized as foreign by the immune system.

• Viral antigens. In tumors caused by oncogenic viruses,

the tumor antigens may be products of the viruses.

Immune Mechanisms of Tumor Rejection

The principal immune mechanism of tumor eradication is killing of tumor cells by CTLs specific for tumor

antigens. The majority of tumor neoantigens that elicit

immune responses in tumor-bearing individuals are

endogenously synthesized cytosolic or nuclear proteins

that are processed by proteasomes and displayed as class

I MHC–associated peptides. Therefore, these antigens

are recognized by class I MHC–restricted CD8+ CTLs,

whose function is to kill cells producing the antigens. The

role of CTLs in tumor rejection has been established in

animal models: tumors can be destroyed by transferring

tumor-reactive CD8+ T cells into the tumor-bearing animals. Studies of many human tumors indicate that abundant CTL infiltration predicts a more favorable clinical

course compared with tumors with sparse CTLs.

CTL responses against tumors are initiated by recognition of tumor antigens on host antigen-presenting

cells (APCs). The APCs ingest tumor cells or their antigens

and present the antigens to naive CD8+ T cells in draining

lymph nodes (Fig. 10.3). Tumors may arise from virtually

any nucleated cell type in any tissue, and, like all nucleated

cells, they usually express class I MHC molecules, but often

they do not express costimulators or class II MHC molecules. We know, however, that the activation of naive CD8+

T cells to proliferate and differentiate into active CTLs

requires recognition of antigen (class I MHC–associated

peptide) on dendritic cells in secondary lymphoid organs

and also costimulation and/or help from class II MHC–

restricted CD4+ T cells (see Chapter 5). How, then, can

tumors of different cell types stimulate CTL responses?

The likely answer is that tumor cells or their proteins are

ingested by the host’s dendritic cells, transported to lymph

nodes draining the site of the tumor, and the protein antigens of the tumor cells are processed and displayed by

class I MHC molecules on the host dendritic cells. This

process, called cross-presentation or cross-priming, was

introduced in Chapter 3 (see Fig. 3.16). Dendritic cells can

also present peptides derived from ingested tumor antigens on class II MHC molecules. Thus, tumor antigens

may be recognized by CD8+ T cells and by CD4+ T cells.

At the same time that dendritic cells are presenting

tumor antigens, they may express costimulators that

provide signals for the activation of the T cells. It is not

known how tumors induce the expression of costimulators on APCs because, as discussed in Chapter 5, the

physiologic stimuli for the induction of costimulators

are usually microbes, and tumors are generally sterile.

A likely possibility is that tumor cells die if their growth

outstrips their blood and nutrient supply, and adjacent

normal tissue cells may be injured and die due to the

invasive tumor. These dying cells release products (damage-associated molecular patterns; see Chapter 2) that

stimulate innate responses. The activation of APCs to

express costimulators is part of these responses.

Once naive CD8+ T cells have differentiated into

effector CTLs, they are able to migrate back to any

site where the tumor is growing, and kill tumor cells

expressing the relevant antigens without a requirement

for costimulation or T cell help.

Immune mechanisms in addition to CTLs may play a

role in tumor rejection. Antitumor CD4+ T cell responses

have been detected in patients, and increased numbers

of CD4+ effector T cells, especially Th1 cells, in tumor

infiltrates are associated with good prognosis. Antitumor

200 CHAPTER 10 Immunology of Tumors and Transplantation

antibodies are also detectable in some cancer patients,

but whether these antibodies protect individuals against

tumor growth has not been established. Experimental

studies have shown that activated macrophages and natural killer (NK) cells are capable of killing tumor cells, and

Th1 responses work largely by activating macrophages,