A redefinition of prognostic staging is being proposed based on the density of the TILs found in primary tumors, among which colorectal cancer has been studied most extensively (19). 2.4% from melanoma (< 0.001). IFN- ELISA demonstrated MHC class ICmediated reactivity of TIL against autologous tumor in 5 of 7 GI cancer patients tested (9% of 188 distinct TIL cultures) and in 9 of 10 melanoma patients (43% of 246 distinct TIL cultures). In these assays, MHC class ICmediated up-regulation of CD137 (4-1BB) expression on CD8+ cells suggested that 0C3% of TILs expanded from GI cancer metastases were tumor-reactive. This study implies that the main challenge to the development of TIL adoptive cell transfer for metastatic GI cancers may not be the in vitro expansion of bulk TILs, but the ability to select and enrich for tumor-reactive T cells. Introduction Cancers arising from the gastrointestinal (GI) tract mucosa rank in the 10 most frequent solid malignancies and causes of cancer-related death (1). Despite the combined use of surgery, chemotherapy, and targeted agents, the great majority of patients with GI adenocarcinomas will die of metastatic disease, and thus new therapies with curative potential are needed. In the past few decades, immunotherapy for solid tumors has emerged as a promising approach (2C4). Treatment AM 103 goals for patients with metastatic melanoma are changing, Ptprc given that the adoptive cell transfer (ACT) of autologous AM 103 tumor-infiltrating lymphocytes (TILs) can mediate complete and durable cancer regression in patients with heavy disease burden, refractory to all other treatments (5). Cancer centers in and outside the United States have begun to offer this form of immunotherapy and report similar response rates, and multicenter trials are expected (6C9). Although the efficacy of TIL-based ACT may be linked to the more immunogenic nature of melanoma compared with other solid cancers, it remains to be determined whether this approach can be adapted for the treatment of common epithelial tumors, AM 103 such as metastatic GI adenocarcinomas. Indirect evidence suggests that T cell immunity may participate in controlling disease progression for GI adenocarcinomas arising in the esophagus, stomach, pancreas, liver, bile ducts, gallbladder, colon, and rectum (10C18). A redefinition of prognostic staging is being proposed based on the density of the TILs found in primary tumors, among which colorectal cancer has been studied most extensively (19). For example, patients with a primary colon cancer highly infiltrated by CD3+ TILs appear to have AM 103 similar disease-free survival, irrespective of whether the tumor is confined to the colon (stage I and II) are has spread to draining lymph nodes (stage III) (17). Genes involved in cytotoxicity and lysis, such as IFN- and granzyme B, appear to be transcribed at lower levels in tumors with aggressive features such as microvascular and perineural invasion compared with tumor with more favorable pathological features (16). Additionally, active mechanisms employed by colon cancer to evade immune recognition have been correlated with lower TIL infiltration and poorer clinical outcomes, such as downregulation of MHC class I (MHC-I) expression by cancer cells (20), and high levels of immunosuppressive molecules such as IDO1 found in the tumor microenvironment (21). In colorectal cancer metastatic to the liver (stage IV), longer survival of patients after complete resection of metastases has been associated with a higher density of CD4+ and CD8+ TILs in metastases and their relative abundance compared with FOXP3+ T cells (putative regulatory T cells [Tregs]) (22, 23). However, in vitro evidence of MHC-restricted recognition of autologous GI cancers by TILs is AM 103 limited. CD4+ TIL clones reactive to a self epitope presented by HLA-DR1 expressed by an autologous colon cancer cell line derived from a liver metastasis and.
A redefinition of prognostic staging is being proposed based on the density of the TILs found in primary tumors, among which colorectal cancer has been studied most extensively (19)