NY‐CO‐58/KIF2C is overexpressed in a variety of solid tumors and induces frequent T cell responses in patients with colorectal cancer

Abstract

NY-CO-58/KIF2C has been identified as a tumor antigen by screening antibody responses in patients with colorectal cancer. However, expression had not consequently been examined, and nothing was known about its ability to induce spontaneous T cell responses, which have been suggested to play a role in the development of colorectal cancer. We analyzed 5 colorectal cancer cell lines, and tumor samples and adjacent healthy tissues from 176 patients with epithelial cancers for the expression of NY-CO-58/KIF2C by RT-PCR and Western Blot. T cell responses of 43 colorectal cancer patients and 35 healthy donors were evaluated by ELISpot following stimulation with 30mer peptides or full-length protein. All cell lines and tumor samples from colorectal cancer patients expressed NY-CO-58/KIF2C on the protein and RNA level, and expression levels correlated strongly with Ki-67 expression (r 5 0.69; p 5 0.0003). Investigating NY-CO-58/KIF2C-specific T cell responses, CD81 T cells directed against 1 or more peptides were found in less than 10% of patients, whereas specific CD4 1 T cells were detected in close to 50% of patients. These T cells were of high avidity, recognized the naturally processed antigen and secreted IFN-c and TNF-a. Depletion of CD4 1 CD25 1 T cells before stimulation significantly increased the intensity of the preexisting response. NY-CO-58/KIF2C is significantly overexpressed in colorectal and other epithelial cancers and expression levels correlate with the proliferative activity of the tumor. Importantly, NY-CO-58/KIF2C was able to induce spontaneous CD4 1 T cell responses of the Th1-type, which were tightly controlled by peripheral T regulatory cells.Colorectal cancer is the second leading cause of cancerrelated death in Western countries with $1 million new cases and over 500,000 deaths per year worldwide. 1 In locally advanced colorectal cancer, surgery combined with the selective application of adjuvant chemotherapy represents the treatment of choice providing cure in a significant number of cases. However, about 40% of patients whose primary tumor has surgically been removed will eventually relapse and ultimately die from the disease.2 Therefore, alternative therapeutic strategies, especially in the adjuvant setting, are needed to improve the prognosis of patients with this malignancy.In the case of colorectal carcinoma, there is strong evidence for a role of the T cell-mediated immune system in controlling the development and progression of the disease. Thus, it has convincingly been demonstrated that infiltration

Integrated NY-ESO-1 antibody and CD8+T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab

“…The reason for the dissociation between antibody responses and antigen-specific CD8 + T-cell responses in these patients is unknown. Such a profile of split T-cell tolerance is uncommon for NY-ESO-1, and is more frequently observed with other tumor antigens, in which there is a dissociation between a strong antibody and/or CD4 + T-cell response and a weak or absent CD8 + T-cell response (50,51). CD8 + T cells with specificity for NY-ESO-1 recognize naturally processed NY-ESO-1 on tumor cells in vitro, and in clinical trials with adoptive CD8 + T-cell transfer, NY-ESO-1-reactive CD8 + T cells have strong antitumor activity (18).…”

Oncogenic role of kinesin proteins and targeting kinesin therapy

“…(40) Upregulation of MACK was detected not only in breast cancer, but also in colorectal, gastric cancer and glioma tissues. (27,41) These data highlight that MCAK is aberrantly regulated in cancer cells, suggesting that overexpressed MCAK might play an oncogenic role in the development of cancer, particularly in breast, gastric and colorectal cancer.…”

KIF-2C expression is correlated with poor prognosis of operable esophageal squamous cell carcinoma male patients

“…KIF-2C localizes to the cytoplasm throughout the cell cycle and is particularly enriched at centrosomes, centromeres/kinetochores, and the spindle midzone during mitosis [9–11] KIF-2C contributes to proper spindle formation [12–15], correction of aberrant attachments of microtubules to chromosomes, and chromosome segregation [10, 11, 16, 17]. The abnormal expression of KIF-2C is associated with abnormal mitosis, chromosomal aberrations, and malignant transformation [15, 17, 18]. Therefore, the deregulation of KIF-2C expression likely plays a role in cancer development and progression.…”

“…Although trace levels of KIF-2C are expressed in healthy organs, its levels are high in testis [18–20] as well as in colorectal cancer, gastric cancer, breast cancer, prostate cancer, and glioma [18–25]. Thus, its expression levels closely resemble those of cancer-testis antigens [26–28].…”