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Originally published as JCO Early Release 10.1200/JCO.2005.95.029 on August 8 2005 © 2005 American Society of Clinical Oncology.
Self-Recognition and Tumor Response to ImmunotherapyDartmouth Hitchcock Medical Center, Lebanon, NH Cancer cells avoid immune destruction by downregulating surface molecules, such as major histocompatibility complex molecules, costimulatory molecules, and tumor-specific antigens that the immune system recognizes as foreign, and by inducing dysfunction or destruction of immune effector cells—T lymphocytes, natural-killer cells, and dendritic cells.1,2 Effector cell function can also be impeded by self-regulatory pathways.3 Effector cell regulation is a dynamic interplay between constitutively expressed tolerance (inhibition), which maintains the immune system in an "off" position normally, and proinflammatory signals (stimulation) induced by exposure to pathogens, including cancer cells. A primary goal of immunotherapy is to upregulate the proinflammatory response and downregulate immune tolerance to cancer cells. Initiation of an inflammatory response to hostile pathogens is generated by natural-killer cells, neutrophils, monocytes, dendritic cells (innate immune system), and other components of the innate immune system through recognition of shared classes of danger signals called pathogen-associated molecular patterns.4 Activation of the innate immune system enhances subsequent recognition of pathogen-specific antigens by the adaptive or acquired immune system (T cells).5 Proinflammatory cytokines or tumor vaccines can mobilize immune effector cells that recognize and destroy cancer, occasionally producing dramatic clinical results, but only in a minority of cancer patients.6 The absence of benefit in the majority of treated patients may be due, in part, to immune inhibition, involving tolerogenic pathways. Central tolerance, the body's ability to eliminate self-reactive T cells, is not an all-or-nothing process.7 The surviving self-reactive T cells have low avidity for self-antigens and, under the right conditions, can become activated, causing autoimmunity. Peripheral tolerance, a network of inhibitory signals and cells, plays a dominant role in downregulating immune response to foreign pathogens, and is primarily responsible for tumor-specific immune inhibition in cancer patients.8 In particular, peripheral tolerance inhibits helper T cells (CD4+) and CD8+ cytolytic T lymphocytes (CTLs), which are specific to tumor antigens and can be effective in tumor destruction. Thus, immune approaches involving CTLs must block peripheral tolerance to be successful. Peripheral tolerance is mediated through a number of signals including the CTL antigen-4 (CTLA-4) molecule, which competes with CD28 (a T-cell stimulatory receptor) for a mutual ligand on antigen-presenting cells (B7.1/B7.2).9 CTLA-4 is also constitutively expressed on a subset of CD4 cells (T regulatory cells [TREG] CD4+CD25+) involved in peripheral tolerance. When CTLA-4 is blocked, CTLs are released from inhibition and the regulatory effects of TREG cells are diminished. Although this creates a permissive environment for tumor-specific CTLs, it also releases the naturally occurring inhibition of self-specific T-cells, thus initiating autoimmunity. In the study by Attia et al,10 patients with metastatic melanoma were vaccinated with two melanoma peptides [gp100:209-217(210M) and gp100:280 to 288(288V)] and subsequently given one of two different dosages of antagonistic anti–CTLA-4 antibody (MDX-010), resulting in two complete remissions and five partial responses in 56 treated patients. Consistent with the notion that blocking CTLA-4 inhibits peripheral tolerance, severe autoimmune-like toxicity was seen in five of seven responding patients, whereas five nonresponding patients had minimal or mild autoimmune toxicity. Studies using stimulatory immune treatments, such as interleukin-2, have also shown an association between autoimmune-like toxicity and clinical outcome, suggesting the involvement of alternate pathways.11,12 In addition, the broader, nonspecific, inflammatory response observed in the study by Attia et al10 is compatible with the possibility that blocking CTLA-4 stimulates the innate immune system, with subsequent activation of adaptive tumor-specific immunity. In the report by Attia et al,10 the majority of 23 patients assessed for immune response exhibited melanoma antigen–specific immunity either to native gp100:209-217 or gp100:280-288 peptides. As noted by the authors, similar immune responses have been seen in patients treated with gp100 vaccines alone; consequently, it is unclear whether CTLA-4 blockade enhances immune response to active vaccination, although it may enhance existent CTLs specific for other, unidentified, melanoma antigens.13 At present, CTLA-4 blockade combined with tumor vaccines is a theoretically promising avenue being pursued in clinical studies. To determine whether anti–CTLA-4 antibody down regulates TREG and activates T cells, Attia et al10 assessed peripheral-blood lymphocyte phenotype for HLA-DR, CD45RO, and CD25 expression in 30 patients. The statistically significant treatment-associated changes observed in these markers suggest a skewing of T-cell response toward a memory phenotype and a decrease in TREG cell number. These changes, like those observed with acquired immunity to native gp100 peptides, were not correlated with clinical response, possibly due to the small number of patients evaluated, although it remains possible that anti–CTLA-4 antibody operates through a different, unidentified, mechanism. Higher doses of anti–CTLA-4 antibody might be more effective in blocking tolerance and enhancing clinical activity, as the authors suggest, but the pharmacodynamic data are not informative regarding whether the dose of anti–CTLA-4 antibody saturates the CTLA-4 binding sites on CTLs and TREG cells, influencing their function. Augmenting tumor-specific antigen CTL response while blocking peripheral tolerance should enhance clinical outcome, and provides the rationale of the study described by Attia et al.10 The effectiveness of blocking CTLA-4 activity as a therapeutic strategy depends on the relative importance of other inhibitory pathways. Tumor-specific CTL anergy (decreased immunity to an antigen) can be regulated by tumor cell–and T-cell–related characteristics. Tumor cells can downregulate the expression of the major histocompatibility complex class I molecules, allowing tumor to escape T-cell recognition and destruction. Tumor cells may also change the expression of immunodominant antigens, resulting in the same effect. In addition, by expressing FasL, tumor cells can eradicate activated T-cells (which have upregulated Fas), through the Fas-FasL death pathway.14 Cancer-induced T-cell–acquired defects, such as loss of T-cell receptor signal transduction components, also render CTLs ineffective. Lack of costimulation of T cells through B7.1/B7.2 will cause anergy. Other regulatory cells, including the less-studied CD8+CD28– suppressor cell, may also be involved with enhancing peripheral tolerance (Crocenzi et al, submitted for publication). It is possible that, in some individuals, a single inhibitory pathway dominates, which may explain the success occasionally seen with single target therapies. However, codominant pathways seem more likely, in which case, treatments exploiting multiple proinflammatory and inhibitory pathways might achieve broader success. Author's Disclosure of Potential Conflicts of Interest
The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) <$10,000 (B) $10,000-99,999 (C)
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5. Ahonen CL, Doxsee CL, McGurran SM, et al: Combined TLR and CD40 triggering induces potent CD8+ T-cell expansion with variable dependence on type I IFN. J Exp Med 199:775-784, 2004 6. Ernstoff MS: Combination cytokine therapy in cancer, in Goldfarb RH, Whiteside TL (eds): Tumor Immunology and Cancer Therapy. New York, NY, Marcel Dekker, 1994, pp 273-279 7. Starr TK, Jameson SC, Hogquist KA: Positive and negative selection of T-cells. Annu Rev Immunol 21:139-176, 2003[CrossRef][Medline] 8. Spiotto MT, Fu YX, Schreiber H: Tumor immunity meets autoimmunity: Antigen levels and dendritic cell maturation. Curr Opin Immunol 15:725-730, 2003[CrossRef][Medline] 9. Alegre ML, Frauwirth KA, Thompson CB: T-cell regulation by CD28 and CTLA-4. Nat Rev Immunol 1:220-228, 2001[CrossRef][Medline]
10. Attia P, Phan GQ, Maker AJ, et al: Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti–cytotoxic T-lymphocyte antigen-4. J Clin Oncol 23:6043-6053, 2005 11. Atkins MB, Mier JW, Parkinson DR, et al: Hypothyroidism after treatment with interleukin-2 and lymphokine-activated killer cells. N Engl J Med 318:1557-1563, 1988[Abstract]
12. Yee C, Thompson JA, Roche P, et al: Melanocyte destruction after antigen-specific immunotherapy of melanoma: Direct evidence of t cell-mediated vitiligo. J Exp Med 192:1637-1644, 2000 13. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al: Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 4:321-327, 1998[CrossRef][Medline]
14. Cardi G, Heaney JA, Schned AR: Expression of Fas(APO-1/CD95) in tumor infiltrating and peripheral blood lymphocytes in patients with renal call carcinoma. Cancer Res 58:2078-2080,1998 Related Article
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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