ONE of the ways her2+ tumors evade her2+ vaccines elucidated

[Lani]

Mechanisms Involved with Tumor Relapse Identified: Researchers work toward creating a tailored breast cancer vaccine [Virginia Commonwealth University]
Researchers at Virginia Commonwealth University's Massey Cancer Center studying the interaction between the immune system and cancer cells have identified interferon gamma as one of the signaling proteins involved with tumor relapse.

The findings may help researchers develop tailored vaccines and other immunotherapeutic strategies to fight a number of cancers. Immunotherapy involves the manipulation of the immune system - by introducing an antibody or lymphocytes, or immunization with a tumor vaccine - to recognize and eradicate tumor cells.

Using a transgenic mouse model of breast cancer, researchers found that interferon gamma, a cytokine or chemical messenger that is produced by cells of the immune system upon activation, plays a role in tumor relapse. In humans, interferon gamma is also produced by white blood cells of the immune system in response to invasion by pathogens or tumors in order to protect the host against infection or cancers. Production of interferon gamma by lymphocytes against tumors is considered a sign of good prognosis; however, recent study findings indicate that this may not be the case. The findings were reported in the March 2007 issue of the European Journal of Immunology, the official journal of the European Federation of Immunological Societies.

"By understanding the molecular mechanisms involved with tumor relapse, we can create tailored vaccines that can induce specific types of immune responses in patients, rather than inducing a broad range of immune responses - some of which may be detrimental or may induce tumor relapse," said lead investigator, Masoud H. Manjili, D.V.M., Ph.D., a member scientist with the Massey Cancer Center.

"Ultimately, we hope to offer a new polypeptide vaccine approach that induces tumor killing without causing HER-2/neu loss. Loss of HER-2/neu is a mechanism that tumors utilize to escape the immune-mediated destruction," he said.

Since 2000, Manjili and his colleagues have been employing animal models of breast cancer to evaluate anti-tumor efficacy of a vaccine formulation they created. This vaccine formulation combines a heat shock protein 110 (HSP110), as an adjuvant, with a tumor antigen HER-2/neu, as a protein target expressed in breast tumors. Adjuvants are agents that are able to modify another agent - basically working as a chemical catalyst.

The work is supported by the National Cancer Institute and the Susan G. Komen Breast Cancer Foundation.


ABSTRACT: HER-2/neu antigen loss and relapse of mammary carcinoma are actively induced by T cell-mediated anti-tumor immune responses [European Journal of Immunology]
Induction of tumor-specific immune responses results in the inhibition of tumor development. However, tumors recur because of the tumor immunoediting process that facilitates development of escape mechanisms in tumors. It is not known whether tumor escape is an active process whereby anti-tumor immune responses induce loss or downregulation of the target antigen in the antigen-positive clones. To address this question, we used rat neu-overexpressing mouse mammary carcinoma (MMC) and its relapsed neu antigen-negative variant (ANV). ANV emerged from MMC under pressure from neu-specific T cell responses in vivo. We then cloned residual neu antigen-negative cells from MMC and residual neu antigen-positive cells from ANV. We found marked differences between these neu-negative clones and ANV, demonstrating that the residual neu-negative clones are probably not the origin of ANV. Since initial rejection of MMC was associated with the presence of IFN-?-secreting T cells, we treated MMC with IFN-? and showed that IFN-? could induce downregulation of neu expression in MMC. This appears to be due to methylation of the neu promoter. Together, these data suggest that neu antigen loss is an active process that occurs in primary tumors due to the neu-targeted anti-tumor immune responses.