The ASCO Post is pleased to present Hematology Expert Review, an ongoing feature that quizzes readers on issues in hematology. In this installment, we begin a new series of articles on cancer immunology and immunotherapy, in which the authors discuss how immunotherapy has become a major pillar of cancer therapy. Drs. Abutalib and Budde will highlight the basic principles of energetic interplay between cancer and immune cells and how such interactions are being successfully exploited in the cancer ecosystem to treat and cure cancer. For each quiz question that follows, select the one best answer. The correct answers and accompanying discussions follow the quiz.
Guest Editors
Syed Ali Abutalib, MD
L. Elizabeth Budde, MD, PhD
Question 1
Which of the following statements about innate immune response is correct?
A. The rapid response by innate immune response to tissue damage is facilitated by somatic rearrangements in pattern recognition receptors.
B. Antigen presentation by innate immune system entails incorporation of small glycopeptides into the binding groove of the major histocompatibility complexes.
C. Toll-like receptors function as pattern recognition receptors to produce antitumor effects.
D. Innate immune response does not interact with the adaptive immune system.
Question 2
Which of the following statements about the adaptive immune response is correct?
A. Plasma cells are responsible for cell-mediated immunity.
B. The adaptive immune response is able to form an immunologic memory.
C. T-cell receptors undergo somatic hypermutations.
D. T-cell–independent antigens predominantly give rise to high-affinity IgG antibodies.
Question 3
Which of the following statements about the clonal selection hypothesis is correct?
A. Antigen-specific clones of lymphocytes develop before and independently of exposure to an antigen.
B. Lymphocyte specificity is determined after exposure to an antigen.
C. The clonal selection hypothesis entails selection of specific clones via immunization.
D. All of the above
Question 4
Which of the following statements about antigen-specific molecules is correct?
A. Similar to T-cell receptors, antibodies are produced only as stationary transmembrane molecules on B cells.
B. The Fc region of antibodies contain the complementarity-determining regions.
C. Most γ/δ T-cell receptors do not recognize antigen in the form of peptide–MHC complexes.
D. The Fab region on antibodies interacts with Fab receptors on macrophages.
Answers to the Quiz
Question 1
Which of the following statements about innate immune response is correct?
Correct Answer: C. Toll-like receptors function as pattern recognition receptors to produce antitumor effects.
Expert Perspective
The cardinal feature of the innate (natural) immune system is the rapid (minutes to hours) and nonspecific (but not to self-antigens, which is known as “tolerance”) response to a broad repertoire of pathogens and in the face of tissue damage. Such response is mediated by germline-encoded pattern recognition receptors, which recognize conserved features of pathogens or damaged cells including cancer cells, termed pathogen-associated molecular patterns or damage (or danger)-associated molecular patterns (“cancer neoantigen”), respectively.
Notably, pattern recognition receptors are expressed by cells of the innate immune system and can be cell membrane–bound or secreted and circulating (eg, antimicrobial peptides). There are several classes of transmembrane pattern recognition receptors including Toll-like receptors (also intracellular), C-type lectin receptors, nucleotide-binding oligomerization domain–like receptors, and retinoic acid–inducible gene-I–like receptors. Given the role of innate immunity in recognizing and clearing the damaged cells, it plays an important role in the immunobiology of cancer. Cells of the innate immune system include granulocytes, monocytes/macrophages, mast cells, dendritic cells, innate lymphoid cells, natural killer cells, natural killer T cells, γ/δ T cells, and epithelial and endothelial cells. Additional components of innate immune system are soluble mediators such as certain cytokines, acute-phase proteins, and the complement system, which are mainly involved in driving the acute inflammatory response. Innate and adaptive immune responses usually collaborate to eliminate pathogens.
Selected innate immune cells such as dendritic cells, natural killer cells, and macrophages function also as antigen-presenting cells to engage adaptive immunity. For example, during an infection or cancer damage, small peptides derived from pathogen proteins are presented in the context of self–major histocompatibility complexes (MHCs) on the surface of antigen-presenting cells to help activate antigen-specific T lymphocytes.
Question 2
Which of the following statements about the adaptive immune response is correct?
Correct Answer: B. The adaptive immune response is able to form an immunologic memory.
Expert Perspective
Adaptive immune responses are generated in the lymphatic system including lymph nodes, spleen, and mucosa-associated lymphoid tissue. Unlike the innate immune response, adaptive immune responses are highly antigen-specific and have the ability to form immunologic memories, which provide long-lasting protection from future challenges. B and T cells are main components of the adaptive (acquired) immune system and are responsible for humoral and cell-mediated immunity, respectively. Under normal circumstances, self-tolerance is maintained by several mechanisms involving the interplay between innate and adaptive immunity. The genes encoding B-cell receptors and T-cell receptors undergo somatic rearrangements to diversify the specificity repertoire; however, only genes encoding B-cell receptors undergo an additional process called somatic hypermutation in the germinal centers, enabling the selection of B cells with stronger antibody/B-cell receptor affinity to antigens.
For most protein antigens, the production of antigen-specific antibody by B cells is dependent on the interaction with CD4+ T-helper cells. However, some antigens are T-cell–independent antigens that can stimulate B cells without assistance from CD4+ T-helper cells. Numerous repetitive epitopes (“highly avid antigens”) are examples of these antigens. These T-cell–independent antigen responses do have a few drawbacks; they do not initiate formation of germinal centers, which leads to lack of memory B cells and high-affinity antibodies. They also do not induce a class switch of immunoglobulins. As a result, the T-cell–independent antigens predominantly give rise to the production of low-affinity IgM antibodies devoid of immunologic memory.
Question 3
Which of the following statements about the clonal selection hypothesis is correct?
Correct Answer: A. Antigen-specific clones of lymphocytes develop before and independently of exposure to antigen.
Expert Perspective
The clonal selection hypothesis was enunciated by Nobel prize winner Macfarlane Burnet in 1957. It correctly predicts that lymphocyte antigen specificities are determined by molecular events prior to any exposure to antigen, and then, in response to exposure to a relevant antigen, the preexisting unique lymphocyte clone will be selected and become activated, proliferate, and differentiate into effector B, antibody-secreting plasma cells, effector cytotoxic (CD8+) and helper (CD4+) T cells, and memory B and T cells.
The antigen-specific cells can proliferate to generate thousands of identical progenies with the same specificity, a process called clonal expansion. Most immune responses involve many different clones—that is, they are polyclonal because even relatively simple antigens bear several different epitopes, each with the specificity to bind to a unique clone. It is estimated that the immune system of an individual can discriminate 107 to 109 distinct antigenic determinants (“lymphocyte repertoire”). The concept of vaccination is an excellent example of an adaptive response and based on the fact that the immune system is primed to mount a secondary immune response with strong and immediate protection.
Question 4
Which of the following statements about antigen-specific molecules is correct?
Correct Answer: C. Most γ/δ T-cell receptors do not recognize antigen in the form of peptide–MHC complexes.
Expert Perspective
T-cell receptors (α/β and γ/δ heterodimers) are produced only as stationary transmembrane molecules, unlike antibodies, which can be produced as circulating molecules (antibodies) or as stationary molecules on the B cells (B-cell receptors). Each α, β, γ, and δ chain on the T-cell receptor contains a variable domain composed of three complementarity-determining regions, which confers antigen-binding specificity and a constant domain. Similarly, the complementarity-determining regions (CDR1, CDR2, and CDR3) within the Fab (fragment antibody binding) domain of an antibody bind the antigens. The Fc (fragment crystallizable) region of antibodies is part of the constant region of the heavy chains; it binds to its corresponding Fc receptors on effector cells to mediate effector functions such as antibody-dependent cellular cytotoxicity.
The α/β T-cell receptors recognize a complex formed by a peptide seated within the groove of an MHC molecule. On the contrary, most γ/δ T-cell receptors do not recognize antigen in the form of peptide–MHC complexes, although MHC-like (“nonclassic MHC”) molecules such as CD1 may present certain antigens (particularly lipids and glycolipids) to some γ/δ T-cell receptors. Other γ/δ T-cell receptors can recognize antigen directly, just as antibody molecules do. n
DISCLOSURE: Dr. Abutalib has reported a financial relationship with AstraZeneca. Dr. Budde has reported financial relationships with ADC Therapeutics, Amgen, AstraZeneca, Genentech/Roche, Gilead Sciences, Merck, and Mustang Therapeutics.
SUGGESTED READINGS
1. Carty SA, Riese MJ, Koretzky GA: T-cell immunity, in Hoffman R, Benz Jr EJ, Silberstein LE, et al (eds): Hematology: Basic Principles and Practice, 8th ed, 2022.
2. Delves PJ, Roitt IM: The immune system: First of two parts. N Engl J Med 343:37-49, 2000.
3. Delves PJ, Roitt IM: The immune system: Second of two parts. N Engl J Med 343:108-117, 2000.
4. Pandya PH, Murray ME, Pollok KE, et al: The immune system in cancer pathogenesis: Potential therapeutic approaches. J Immunol Res 2016:4273943, 2016.
5. Briquez PS, Hauert S, de Titta A, et al: Engineering targeting materials for therapeutic cancer vaccines. Front Bioeng Biotechnol 8:19, 2020.
