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Journal of Clinical Oncology, Vol 26, No 9 (March 20), 2008: pp. 1563 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.6612
In ReplyCentre for Cancer Treatment, Mount Vernon Hospital, Northwood, United Kingdom We thank Professors Formenti and Demaria for their kind comments on our recent review. They suggest an additional and intriguing hypothesis to explain the poor results from neoadjuvant cisplatin before radiation, by virtue of a less efficient immune response to dying cells damaged by chemotherapy alone compared with chemoradiotherapy. It is certainly not easy to account for the improved outcome observed after complete pathologic response in a primary tumor after chemoradiotherapy. Patients with apparently clinically localized disease and high risk of distant failure, as in locally advanced unresectable T4 rectal cancer, should not benefit from chemoradiotherapy even if a complete pathologic response is achieved. Significant systemic effects are not expected, and local control should not be relevant if subclinical micrometastases are already present. Yet the 10% to 15% of patients with rectal cancer who achieve a pathologic complete response do have a surprisingly favorable outcome.1 In contrast, complete pathologic response to chemotherapy alone is a rare phenomenon in solid tumors where neoadjuvant chemotherapy alone is routinely employed. Pathologic complete response could represent an indirect way of promoting distant abscopal effects. Normally, the immune system is tolerant to antigens on growing tumors. Innate factors induced in response to dying cancer cells may influence the clinical outcome of anticancer treatment. Hence, it is possible that with the damage sustained from chemoradiotherapy by the tumor cells in achieving a complete clinical response, this tolerance could be broken down, and dead tumor cells could be presented in a recognizable form to T cells. It has long been recognized that microsatellite instability is associated with killer T cells and apoptosis.2 Some studies have suggested that high-frequency microsatellite instability in rectal cancer is associated with high rates of pathologic complete response after neoadjuvant chemoradiotherapy with fluorouracil and irinotecan. Current theories regarding the activity of dendritic cells, which can be recognized by T cells, do not make immune-based abscopal effects an entirely fanciful notion. We know that the interaction among the tumor, the stroma, and the immune system may play a critical role in outcome because tumor growth and metastases clearly depend on the availability of angiogenic and various growth factors. Yet death receptors such as FAS/CD95 and MHC1 can also be upregulated by radiotherapy, and could just as easily have secondary vascular effects with expression of adhesion molecules produced by dying endothelial cells. The question then remains as to whether the immune response to cell death after chemoradiotherapy is so different from that after chemotherapy alone. It should be possible to examine cell death in response to neoadjuvant chemotherapy by studying circulating T cells.3,4 Also, the kinetics of infiltrating leukocyte subsets could be followed after chemotherapy. This would determine the effects on infiltrating immune cells. The clearance of apoptotic tumor cells and complement fractions could also be measured.5 We would therefore encourage Professors Formenti and Demaria to collect the data to test this hypothesis. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES 1. Capirci C, Valentini V, Rodel F, et al: Prognostic value of pathological complete response after neoadjuvant chemo-radiotherapy in locally advanced rectal cancer: A pooled analysis on 566 patients. Radiother Oncol 81:s76, 2006 (suppl 1; abstr 193) 2. Dolcetti R, Viel A, Doglioni C, et al: High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability. Am J Pathol 154:1805-1813, 1999 3. Curiel TJ, Coukos G, Zou L, et al: Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942-949, 2004[CrossRef][Medline] 4. Yang Y, Huang CT, Huang X, et al: Persistent Toll-like receptor signals are required for reversal of regulatory T cell-mediated CD8 tolerance. Nat Immunol 5:508-515, 2004[CrossRef][Medline] 5. Rovere P, Peri G, Fazzini F, et al: The long pentraxin PTX3 binds to apoptotic cells and regulates their clearance by antigen-presenting dendritic cells. Blood 96:4300-4306, 2000
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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