Local Radiation Therapy Inhibits Tumor Growth through the Generation of Tumor-Specific CTL: Its Potentiation by Combination with Th1 Cell Therapy

Abstract

Radiation therapy is one of the primary treatment modalities for cancer along with chemotherapy and surgical therapy. The main mechanism of the tumor reduction after irradiation has been considered to be damage to the tumor DNA. However, we found that tumor-specific CTL, which were induced in the draining lymph nodes (DLN) and tumor tissue of tumor-bearing mice, play a crucial role in the inhibition of tumor growth by radiation. Indeed, the therapeutic effect of irradiation was almost completely abolished in tumor-bearing mice by depleting CD8 + T cells through anti-CD8 monoclonal antibody administration. In mice whose DLN were surgically ablated or genetically defective (Aly/Aly mice), the generation of tetramer + tumor-specific CTL at the tumor site was greatly reduced in parallel with the attenuation of the radiation-induced therapeutic effect against the tumor. This indicates that DLN are essential for the activation and accumulation of radiationinduced CTL, which are essential for inhibition of the tumor. A combined therapy of local radiation with Th1 cell therapy augmented the generation of tumor-specific CTL at the tumor site and induced a complete regression of the tumor, although radiation therapy alone did not exhibit such a pronounced therapeutic effect. Thus, we conclude that the combination treatment of local radiation therapy and Th1 cell therapy is a rational strategy to augment antitumor activity mediated by tumor-specific CTL.

An Abscopal Response to Radiation Therapy in a Patient with Metastatic Non-Small Cell Lung Cancer: A Case Report

“…The antitumor activity of cytotoxic T cells can be observed in the non-irradiated field. Such Abscopal responses can be achieved by irradiating either primary or metastatic tumors [13][14][15][16][17][18].…”

Establishment of a stable T lymphoma cell line transduced with HLA-A^|^lowast;24:02-restricted WT1-specific TCR genes and its application to antigen-specific immunomonitoring

“…Thus, this may become a promising tool for developing TCR gene immunotherapy. We recently demonstrated that introducing Th1-dominant immunity is essential for inducing fully activated CTLs and immunological memory in tumor-bearing hosts (9,18,19,30). It has also been demonstrated that a mixture of various synthetic long peptides derived from naturally occurring sequences of HPV-16 oncoproteins was superior to short tumor peptides in terms of inducing complete or partial response in vulvar intraepithelial neoplasia (12).…”

Increased neutrophil-to-lymphocyte ratio is a novel marker for nutrition, inflammation and chemotherapy outcome in patients with locally advanced and metastatic esophageal squamous cell carcinoma

“…Currently, it is widely accepted that inflammatory cells, which are present in the tumor microenvironment, and the tumor immune response, which is activated by ionizing radiation, significantly affect tumor development (28)(29)(30)(31). This tumor-generated inflammatory response may result in an increased propensity for apoptosis, angiogenesis and DNA damage by upregulating cytokines and inflammatory mediators.…”