2010 - Transplantomics and Biomarkers in Transplantation


THE ANTIBIOME AND TRANSPLANTATION

6.1 - COMMON SIGNATURES OF REJECTION

Presenter: Francesco M., Marincola, Bethesda, USA
Authors: Francesco M. Marincola


COMMON SIGNATURES OF REJECTION
Francesco M. Marincola,
Chief Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center; Associate Director, Trans-NIH Center for Human Immunology, National Institutes of Health & Director, CC/CHI FOCIS Center of Excellence, Bethesda, MD, USA
Learning Objectives:
1. Learn about biomarkers that are relevant to cancer rejection during immune therapy.
2. Lean about a common mechanism that seems to be responsible for the rejection of tissues through immune activation.
3. Discuss how this information could be used to improve treatment.
COMMON SIGNATURES OF REJECTION
Ena Wang and
Francesco M. Marincola

Infectious Disease and Immunogenetics Section (IDSI), Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, MD, USA.
Fundamental strides in the understanding of the molecular basis of tumor rejection were made in the last decade thanks to observational studies performed at relevant time points in human cancerous tissues. The following concepts emerged: immune surveillance against tumors is a likely occurrence. When cancer cells evolve to escape the ongoing immune defense, the neoplastic process reaches a clinically observable phase. By necessity, at this clinical stage, escape mechanisms override anti-cancer mechanisms for tumors to be observable. When cancers become established, two molecular phenotypes can usually be observed: one is characterized by a tumor microenvironment infiltrated by immune cells bearing transcriptional signatures consistent with a status of partial activation. Although incapable of dramatically affecting tumor growth, immune infiltration bears a favorable prognostic and/or predictive connotation on the natural history of the disease or its responsiveness to therapy. In this presentation, we will discuss the significance of transcriptional signatures observed in pre-treatment biopsies as predictive of responsiveness to biological therapy. Moreover, we will discuss the transcriptional signatures observable during and after therapy documenting the switch from chronic to acute inflammation that leads to tumor rejection. Finally, we will discuss how mechanisms leading to tumor rejection, largely overlap those associated with other aspects of immune-mediated tissue-specific destruction such as allograft rejection, graft versus host disease, acute clearance of pathogen and autoimmunity. These include overlapping yet distinct themes that

are consistently present when TSD occurs:
• the STAT-1/IRF-1/T-bet/IFN-γ, IL-15 path
• the Granzyme A/B, TIA-1 pathway
• the CXCR3 ligand chemokine pathway
• the CCR5 ligand chemokine pathway
Understanding the basic mechanisms that can switch a chronic inflammatory process incapable of eradicating its cause into an acute reaction with the power of destroying completely the triggering cause, may shed insights that may guide the development of novel therapeutic strategies.


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