Our findings demonstrate that our in vivo CTLA-4 blockade-based T cell expression cloning can identify immunogenic cancer antigens with potential relevance for human immunotherapy.
In this study, we aimed to investigate the association of cancer with the frequencies and roles of CTLA-4/+49A > G (exon 1) and -318C > T (promoter), and CD28/IVS3 + 17T > C (intron 3 position + 17).
The cytotoxic T lymphocyte antigen 4 gene (CTLA4) is a critical regulator of T-cell activation and it is an important therapeutic target for cancer and autoimmune diseases.
Genotyping in 5,832 individuals with cancer and 5,831 control subjects in northern and southern Chinese populations showed that the CTLA-4 49AA genotype had an odds ratio of 1.72 (95% confidence interval, 1.50-2.10; P = 3.4 x 10(-7)) for developing cancer compared with the 49GG genotype.
Although blockade of CTLA-4 with Ab in humans undergoing cancer immune therapy has led to some cases of inflammatory bowel disease, spontaneous animal models of colitis that depend upon modulation of B7 interactions have not been previously described.
We developed a mouse expressing human instead of mouse CTLA-4, allowing us to evaluate the independent contributions of CTLA-4 blockade of each T cell compartment during cancer immunotherapy in an in vivo model of mouse melanoma.
These findings suggest that increased sCTLA4 may contribute in CTLA4-induced suppression of tumor immunity and provide explanations for the widely reported association of CTLA4 gene with cancer.
Compared with the common CTLA-4 +49G > A GG genotype, the carriers of variant genotypes (CTLA-4 +49 GC/CC) had a 1.24-fold elevated risk of cancer (95% CI = 1.18-1.32, P < 0.05) under the dominant genetic model, as estimated using a fixed effect model.
The objective of the current study was to conduct a meta-analysis investigating the association between polymorphisms in the CTLA-4 gene and the risk of cancer.
Several polymorphisms within the CTLA-4 gene have been associated with an increased risk of developing autoimmune diseases and, very recently, with susceptibility to human cancer.
Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene polymorphisms have been associated with many autoimmune diseases and malignancy susceptibility, but the relationship between CTLA-4 and cervical cancer is still controversial.
Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the relationship between CTLA4 gene polymorphisms and cancer susceptibility were calculated by stata 11 software.
These results reveal a CTLA-4-PKC-η signaling axis required for contact-dependent suppression and implicate this pathway as a potential cancer immunotherapy target.
The association between cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene -1722T/C polymorphism (rs733618) and cancer has been widely assessed, and a definitive conclusion remains elusive.
It is therefore the most extensively studied polymorphism among all CTLA-4 genetic variants and contributions to increasing the likelihood of developing cancer are well known in various populations, especially Asians.
Importantly, CTLA4 expression is observed in T cells of patients with blood malignancies, and CTLA4(apt)-STAT3 siRNA treatment of immunodeficient mice bearing human T cell lymphomas promoted tumor cell apoptosis and tumor growth inhibition.
Recent studies suggest that the cancer immunotherapy based on the blockade of the CTLA-4-mediated inhibitory pathway is efficacious only in select populations, predominantly for immunogenic tumors or when delivered in combination with modalities that can break immunologic tolerance to tumor antigens.
Currently, both the combination of targeted drugs and the invention of effective immunomodulating antibodies, e.g., anti-CTLA4 as well as anti-PD1, hold great promise to proceed on the way to individualized disease control, if not, as a remote aim, cure of this deadly cancer.