MOLECULAR BASES OF THE INTERACTIONS BETWEEN HUMAN NEUTROPHILS AND OTHER TUMOR-INFILTRATING LEUKOCYTE TYPES. (AIRC 2008-2010))

Starting date
January 1, 2009
Duration (months)
36
Managers or local contacts
Cassatella Marco Antonio
URL
http://www.airc.it/
Keyword
neutrophils, Th lymphocytes, NK cells

The innate immune system exerts a fundamental role in the detection and early removal of
transformed cells. Within the immune system, natural killer (NK) cells and T lymphocytes,
particularly CD8+ T cells, have been widely recognized as key actors in the cancer
immunosurveillance process, with their cooperation with other cells of the innate immune system
being of primary importance. In this context, the role of neutrophils in the whole cancer
immunosurveillance process and/or in the modulation of tumor-infiltrating leukocyte types is either
unknown (for instance with respect to NK cells) or poorly documented (for instance with respect to
T lymphocytes), even though neutrophils certainly represent a key component of the innate immune
system that is present in the tumour microenvironment. In addition, and as emerged from the work
of the applicant's laboratory during the last years, neutrophils possess the capacity to produce and
release a number of proinflammatory and immunoregulatory cytokines, a fact that has re-evaluated
the importance, the role and the physiological and pathological significance of neutrophils in the
pathogenesis of inflammatory, infectious, autoimmune and neoplastic diseases.
Given these premises, the current research project proposes to investigate the existence, the
properties and the consequences of a cross-talk: i) between neutrophils and NK cells; and; ii)
between neutrophils and T lymphocytes (CD4+, CD8+ and the recently identified Th17 cells).
Moreover, since extensive literature has highlighted a primary role of dendritic cells (DC) in
modulating NK cell activity, as well as the existence of a reciprocal activation between DC and
neutrophils, our proposal also aims at investigating the cross-talk between neutrophils and NK cells
in the presence or the absence of the various circulating DC subtypes (indirect cross-talk), including
the myeloid DC (mDC) and the plasmacytoid DC (pDC). After the initial characterization of the
direct and/or indirect role of neutrophils in modulating the NK cell activities, the research project
aims at the definition of the molecular mechanisms and mediators regulating the phenomena that
will be uncovered. Since our preliminary data clearly indicate that activated CD4+ and CD8+ T
cells can both directly delay spontaneous apoptosis of neutrophils, we propose to identify the
molecular mechanisms and related mediators involved in such anti-apoptotic effects, to determine if
CD4+ and CD8+ T cells act through similar or different molecular mechanisms. Finally, we propose
to evaluate the cross-talk between neutrophils and Th17 cells and its potential implications in
tumour growth and angiogenesis, since Th17 cells, in addition to their predominant role in
inflammation and neutrophil recruitment, were recently linked to cancer. The relevance of our
research proposal relies on the characterization of new mechanisms employed by the innate immune
system for the cancer immunosurveillance process, along with the identification of novel effector
roles of neutrophils in the tumour microenvironment. These studies will be of primary importance for the identification of new targets able to potentiate the removal of cancerous cells by the innate
immune system.

Sponsors:

A.I.R.C. Associazione Italiana per la Ricerca sul Cancro
Funds: assigned and managed by the department
A.I.R.C. Associazione Italiana per la Ricerca sul Cancro
Funds: assigned and managed by the department

Project participants

Martin Pelletier
Nicola Tamassia
Temporary Assistant Professor

Activities

Research facilities