Combination Chemotherapy and Radiation of Human Squamous Cell Carcinoma of the Head and Neck Augments CTL-Mediated Lysis

Abstract

Purpose: 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. Experimental Design: 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.

Cancer Vaccines: Moving Beyond Current Paradigms

“…Still another new paradigm to exploit in vaccine combination therapies is the phenomenon that certain standard of care therapeutics can actually alter the phenotype of tumor cells to render them more susceptible to T-cell -mediated lysis. This has been shown in a series of preclinical studies (48,49). Sublethal doses of radiation delivered via external beam have been shown to up-regulate tumor-associated antigens, fas, and/or adhesion molecules and/or down-regulate antiapoptotic genes, subsequently rendering these phenotypically altered tumor cells more susceptible to antigen-specific T-cell -mediated lysis.…”

“…Sublethal doses of radiation delivered via external beam have been shown to up-regulate tumor-associated antigens, fas, and/or adhesion molecules and/or down-regulate antiapoptotic genes, subsequently rendering these phenotypically altered tumor cells more susceptible to antigen-specific T-cell -mediated lysis. Chemotherapeutic agents, such as 5-fluorouracil (50), cisplatin, and gemcitabine (48), have also been used in sublethal doses inducing similar alterations of tumor cell phenotype and subsequent susceptibility to T-cell -mediated lysis. This may ultimately lead to another paradigm shift in vaccine combination therapies (i.e., when a patient does not respond to a drug or radiation therapy due to its lack of ability to lyse tumor cells, it may continue to be used with vaccine therapy due to its ability to augment vaccine-induced T-cell lysis of tumor).…”

Combining Radiotherapy and Cancer Immunotherapy: A Paradigm Shift

“…Proinflammatory cytokines induced by radiation include interleukin 1β, tumor necrosis factor α and type 1 and 2 interferons (30,(33)(34)(35)(36). In addition, tumor cells that receive sublethal doses of radiation undergo phenotypic changes that enhance their susceptibility to immune effectors (37)(38)(39). Enhanced expression of death receptors (40,41), MHC class 1 molecules (37,42,43), costimulatory molecules (44), adhesion molecules (45)(46)(47), and stress-induced ligands (48-50) on tumor cells exposed to radiation increased their recognition and killing by T cells in vitro and/or in vivo in several cancer models.…”

Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial

“…Although the results of this trial need confi rmation, a number of hypotheses can be off ered as to why active antigen-specifi c immunotherapy might show a favourable eff ect in patients treated with concurrent and not sequential chemoradiotherapy. Results of an in-vitro study using a head and neck model cell line 26 showed that cytotoxic T-cell mediated lysis directed against MUC1 was enhanced by previous treatment with concomitant chemoradiotherapy compared with either modality alone. Additionally, two studies by similar study teams 27,28 reported that some chemotherapeutic agents can induce immuno genic cell death whereas others induce tolero genic cell death.…”