Low Surface Expression of B7-1 (CD80) Is an Immunoescape Mechanism of Colon Carcinoma

Abstract

Artificially enforced expression of CD80 (B7-1) and CD86 (B7-2) on tumor cells renders them more immunogenic by triggering the CD28 receptor on T cells. The enigma is that such B7s interact with much higher affinity with CTLA-4 (CD152), an inhibitory receptor expressed by activated T cells. We show that unmutated CD80 is spontaneously expressed at low levels by mouse colon carcinoma cell lines and other transplantable tumor cell lines of various tissue origins. Silencing of CD80 by interfering RNA led to loss of tumorigenicity of CT26 colon carcinoma in immunocompetent mice, but not in immunodeficient Rag À/À mice. CT26tumor cells bind CTLA-4Ig, but much more faintly with a similar CD28Ig chimeric protein, thus providing an explanation for the dominant inhibitory effects on tumor immunity displayed by CD80 at that expression level. Interestingly, CD80-negative tumor cell lines such as MC38 colon carcinoma and B16 melanoma express CD80 at dim levels during in vivo growth in syngeneic mice. Therefore, low CD80 surface expression seems to give an advantage to cancer cells against the immune system. Our findings are similar with the inhibitory role described for the dim CD80 expression on immature dendritic cells, providing an explanation for the low levels of CD80 expression described in various human malignancies. (Cancer Res 2006; 66(4): 2442-50)

Chimeric PD-1:28 Receptor Upgrades Low-Avidity T cells and Restores Effector Function of Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy

“…Depicted is the amount of cytokine secreted by 25,000 CD8 þ cytokine secretion and degranulation and supports TCR-independent programs downstream of AKT/mTOR, such as survival, cellcycle progress, glucose consumption, and restoration of lytic proteins, which are particularly valuable in a restricting environment (23,24). Human CD8 þ T cells lose CD28 costimulatory receptor expression during effector-cell differentiation (34), and epithelial cancers generally do not express cognate ligands CD80 or CD86 (35,36); thus, T cells are unable to receive proper costimulation in this situation. In the context of ATT, low-avidity T cells may not be sufficiently active for tumor elimination due to low functional responses.…”

Immunization with MHC class I-negative but not -positive HPV16-associated tumour cells inhibits growth of MHC class I-negative tumours

“…Therefore, the experiments analyzing the crossreactivity between the MK16 and the TC-1/A9 cell lines were performed. These two tumour cell lines were selected because they expressed the same tumour rejection antigens (E6 and E7), both were phenotypically MHC class Inegative and they were distinct in the expression of molecules important for interaction with T lymphocytes (CD54, CD80, B7-H2), an expression level of which could also contribute to the immune escape (46). Importantly, these cell lines were different in their origin (lungs vs. kidney).…”

Agonist Anti-CD137 mAb Act on Tumor Endothelial Cells to Enhance Recruitment of Activated T Lymphocytes

“…CT26, EMT6, and Lewis lung carcinoma (LLC) tumor cell lines (38) were from ATCC, and authenticated and quality controlled by the services of the cell bank at Bristol-Myers Squibb by DNA testing. Cells were cultured in complete RPMI medium [RPMI 1640 with Glutamax (Gibco, Invitrogen) containing 10% heat-inactivated FBS (Sigma-Aldrich), 100 IU/mL penicillin and 100 mg/mL streptomycin (Biowhittaker), and 5 Â 10 À5 mol/L 2-mercaptoethanol (Gibco)].…”