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Immune Recognition of Self in Immunity Against Cancer

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Immune Recognition of Self in Immunity Against Cancer Immune recognition of self in immunity against cancer Alan N. Houghton, José A. Guevara-Patiño J Clin Invest. 2004;114(4):468-471. https://doi.org/10.1172/JCI22685. Commentary Most antigens expressed by human cancer cells and recognized by host T cells and antibodies are nonmutated self antigens — molecules also expressed on the surface of normal cells. These self antigens are ineffective at triggering immune responses against cancer cells, which provides one explanation for the difficulties in trying to immunize against human cancer. A new study describes how tumors can avoid recognition by the immune system and how enhancing the affinity of the interaction between a self antigen and the MHC-I molecule may lead to cancer immunity. Find the latest version: https://jci.me/22685/pdf commentaries and injury. J. Clin. 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A novel domain in AMP- surgery. A meta-analysis of the 5 international ran- riboside. Lack of effect in rabbit cardiomyocytes activated protein kinase causes glycogen storage domized trials. The Multicenter Study of Periop- and human erythrocytes, and inhibition in FTO- bodies similar to those seen in hereditary cardiac erative Ischemia (McSPI) Research Group. JAMA. 2B rat hepatoma cells. Biochem. J. 305:913–919. arrhythmias. Curr. Biol. 13:861–866. 277:325–332. 18. Andersson, U., et al. 2004. AMP-activated protein 11. Polekhina, G., et al. 2003. AMPK b-Subunit targets 15. Gadalla, A.E., et al. 2004. Distinct mechanisms under- kinase plays a role in the control of food intake. metabolic stress-sensing to glycogen. Curr. Biol. lie the activation of rat brain AMP-activated protein J. Biol. Chem. 279:12005–12008. 13:867–871. kinase and the inhibition of excitatory synaptic trans- 19. Minokoshi, Y., et al. 2004. AMP-kinase regulates 12. Scott, J.W., et al. 2004. CBS domains form energy- mission by AICA riboside (Acadesine) in area CA1 of food intake by responding to hormonal and sensing modules whose binding of adenosine rat hippocampus. J. Neurochem. 88:1272–1282. nutrient signals in the hypothalamus. Nature. ligands is disrupted by disease mutations. J. Clin. 16. Corton, J.M., Gillespie, J.G., Hawley, S.A., and Har- 428:569–574. Immune recognition of self in immunity against cancer Alan N. Houghton and José A. Guevara-Patiño The Swim Across America Laboratory of Tumor Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. Most antigens expressed by human cancer cells and recognized by host T cells methylation of nucleotides in promoter and antibodies are nonmutated self antigens — molecules also expressed on the regions that control gene expression. These surface of normal cells. These self antigens are ineffective at triggering immune deleted or silent genes are incapable of pro- responses against cancer cells, which provides one explanation for the difficul- ducing antigenic targets for the immune ties in trying to immunize against human cancer. A new study describes how system, but mutated protooncogenes, tumors can avoid recognition by the immune system and how enhancing the tumor suppressor genes, or other self genes affinity of the interaction between a self antigen and the MHC-I molecule may might generate mutant protein products lead to cancer immunity (see the article beginning on page 551). that could serve as suitable antigens. An accumulation of genetic alterations The self/nonself paradigm provides a logical and useful description in protooncogenes and tumor suppressor Immunologists generally agree that the of how the immune system responds to genes leads to profound changes in nor- immune system was shaped through evo- exogenous microbes that cause disease. mal cells, including immortality, a block lution by the necessity of discriminating in terminal differentiation, an ability to nonself pathogens from self tissues (1). Recognition of cancer invade normal tissues and recruit new This distinction is extremely important by the host’s immune system blood vessels, and the potential to metas- for the survival of multicellular organ- Understanding and achieving immunity tasize to distant organs (3). However, isms. Some strategies for the recogni- to cancer does not fit neatly into the self/ because the immune system is trained not tion of nonself pathogens are clear-cut. nonself paradigm because cancer is not to respond to self molecules (in order to For example, receptors such as toll-like an exogenous pathogen, but rather arises avoid autoimmunity), antigenic changes receptors on host leukocytes bind to cer- from normal host cells. In this regard, in malignant cells that are created by tain bacterial or fungal molecules, lead- cancer antigens recognized by the human individual mutations can be rather subtle ing to mobilization of host defenses by immune system are self or mutated self from the standpoint of the immune sys- signaling the synthesis of molecules that molecules (2). Explaining the genetic tem — cancer cells still utilize essentially initiate innate and adaptive immune basis for the pathogenesis of cancer is the same cellular molecules as healthy responses. The adaptive immune system, necessary to understanding the difficul- cells to regulate growth and survival (3). with its diversity of T cell receptors (TCRs) ties that the immune system has in recog- Perhaps mutations in self proteins can and antibodies, uses even more precise nizing cancer cells. be viewed as generating nonself proteins, mechanisms for the recognition of non- Protooncogenes and tumor suppres- comparable to foreign proteins from self pathogens. This view of self/nonself sor genes are normal cellular genes that pathogens or other species. This argument control crucial cell functions, particularly has been used as the basis for conduct- Nonstandard abbreviations used: T cell receptor growth and survival (3). Mutations in these ing experiments in mice for the study of (TCR). genes lead to the emergence of cancer. In tumor immunity using tumors expressing Conflict of interest: The authors have declared that no addition, loss of expression of tumor sup- viral or chicken proteins. conflict of interest exists. pressor genes contributes to malignant T cells, which are immune cells crucial Citation for this article: J. Clin. Invest. 114:468–471 (2004). transformation through major deletions for rejecting tumors, use their TCRs to doi:10.1172/JCI200422685. in their genetic sequences or silencing by recognize short antigenic peptides bound 468 The Journal of Clinical Investigation http://www.jci.org Volume 114 Number 4 August 2004 commentaries T cell–dependent immunity against mutated self antigens on tumors Can cancer cells with mutated self peptides stimulate host T cells? As few as two or three distinct mutations in different cel- lular protooncogenes can induce malig- nant transformation and tumorigenicity of normal rodent cells (3, 4). In this reduc- tionist view, a total of only two mutations in two different cellular proteins produce tumors. The problem for host T cells becomes searching for these two mutations against the backdrop of the thousands of nonmutated proteins in the cell — which is like searching for a needle in a haystack. The reader may be aware that T cells can use their TCRs to discriminate even single amino acid changes in peptides. Thus, acti- vated T cells might be capable of surveying for cancer cells expressing rare mutated self peptides bound to MHC-I or -II molecules, leading to destruction of those cells. In sup- port of this argument, classical experiments in mice have shown that T cells are capable of rejecting mutagen-induced tumors (5). For tumors in mice induced by exposure to strong mutagens, T cell–dependent immu- nity is directed against antigens that are mutated self peptides (6, 7). Do T cell responses to mutated self anti- gens reveal how immunity against cancer is generated? Not exactly. Tumors that Figure 1 are elicited by short, intense exposure of Yu et al. (16) investigate how host CD8+ T cells respond to a self peptide presented by MHC-I molecules on tumor cells. The self peptide binds relatively weakly to host MHC molecules. The rodents to potent carcinogens carry large self peptide ITDQVPFSV (single letter amino acid code), expressed by melanoma cells and numbers of mutations, and these tumors normal pigment cells, binds with low affinity to MHC-I HLA-A*0201 molecules. A mutated form of arise over weeks or several months. These the self peptide, IMDQVPFSV with a threonine to methionine substitution at the second amino experimental models do not adequately acid position, has a high affinity for MHC-I molecules because methionine residues at the second reflect the pathogenesis of most human position are more favorable to anchor the peptide to HLA-A*0201 molecules. Naive CD8+ T cells cancers, which result from multiple dis- against the self peptide are present in the immune repertoire, but they do not respond to either crete mutations accumulated sequentially tumor cells presenting the weak self peptide or to immunization with the self peptide because of over decades (3).
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