Combination chemotherapy and radiation of human squamous cell carcinoma of the head and neck augments CTL-mediated lysis.
OBJECTIVE
The combination of systemic multiagent chemotherapy (5-fluorouracil + cisplatin) and tumor irradiation is standard of care for head and neck squamous cell carcinoma (HNSCC). Furthermore, it has been shown that sublethal doses of radiation or chemotherapeutic drugs in diverse cancer types may alter the phenotype or biology of neoplastic cells, making them more susceptible to CTL-mediated cytotoxicity. However, little is known about the potential synergistic effect of drug plus radiation on CTL killing. Here, we examined whether the combination of two chemotherapeutics and ionizing radiation enhanced CTL-mediated destruction of HNSCC more so than either modality separately, as well as the basis for the enhanced tumor cell lysis.


METHODS
Several HNSCC cell lines with distinct biological features were treated with sublethal doses of cisplatin and 5-fluorouracil for 24 hours and with 10-Gy irradiation. Seventy-two hours postirradiation, tumor cells were exposed to an antigen-specific CD8+ CTL directed against carcinoembryonic antigen or MUC-1.


RESULTS
In three of three tumor cell lines tested, enhanced CTL activity was observed when the two modalities (chemotherapy and radiation) were combined as compared with target cells exposed to either modality separately. CTL-mediated lysis was MHC restricted and antigen specific and occurred almost entirely via the perforin pathway. Moreover, the combination treatment regimen led to a 50% reduction in Bcl-2 expression whereas single modality treatment had little bearing on the expression of this antiapoptotic gene.


CONCLUSIONS
Overall, these results reveal that (a) CTL killing can be enhanced by combining multiagent chemotherapy and radiation and (b) combination treatment enhanced or sensitized HNSCC to the perforin pathway, perhaps by down-regulating Bcl-2 expression. These studies thus form the rational basis for clinical trials of immunotherapy concomitant with the current standard of care of HNSCC.
Gelbard
Alexander
A
Howard Hughes Medical Institute, Research Scholar's Program at the NIH, Bethesda, MD, USA.
Garnett
Charlie T
CT
Abrams
Scott I
SI
Patel
Vyomesh
V
Gutkind
J Silvio
JS
Palena
Claudia
C
Tsang
Kwong-Yok
KY
Schlom
Jeffrey
J
Hodge
James W
JW
D000951:Antigens, Neoplasm / Q000032:analysis / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology; D002272:Carcinoembryonic Antigen / Q000032:analysis / Q000276:immunology; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology / Q000528:radiation effects; D002945:Cisplatin / Q000494:pharmacology; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006258:Head and Neck Neoplasms / Q000276:immunology / Q000473:pathology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D008562:Membrane Glycoproteins / Q000032:analysis; D018396:Mucin-1; D009077:Mucins / Q000032:analysis / Q000276:immunology; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D013602:T-Lymphocytes, Cytotoxic / Q000737:chemistry / Q000166:cytology / Q000276:immunology*; D013997:Time Factors
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D002272:Carcinoembryonic Antigen; C060192:MUC1 protein, human; D008562:Membrane Glycoproteins; D018396:Mucin-1; D009077:Mucins; D052899:Pore Forming Cytotoxic Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D054353:Perforin; D018799:Intercellular Adhesion Molecule-1; D002945:Cisplatin; D005472:Fluorouracil