Implications of adaptive immune response modulation in cancer control

Abstract

The immune system has the ability to recognize damage-associated molecular patterns (DAMPs) generated by tumor growth, which can lead to its elimination or continued inflammation. The initial innate immune response sets the stage for a specific adaptive immune reaction that is equipped to eradicate the neoplastic lesion, and often happens long before the disease becomes clinically detectable. When antitumor immunosurveillance fails, the resulting tumors frequently contain immune cells that tend to acquire a hypofunctional phenotype characterized by anergy and exhaustion. The object of our proposal is the study of tumor-infiltrating T lymphocytes and, more precisely, the test of an immunomodulatory approach that has the potential to restore the lymphocyte antitumor function. For this purpose, we will use syngeneic murine models of solid tumor and leukemia in which we will try to revert the state of hyperactivation and hypofunctionality of lymphocytes, in order to control the neoplastic growth. Lymphocytes will be isolated from the tumors of animals that receive or not the immune modulation protocol; thereafter, the cells will be phenotypically examined by flow cytometry for the expression of surface markers of anergy, exhaustion and hyperactivation, as well as for proliferative capacity. This characterization will be completed by determining the metabolic profile, susceptibility to apoptosis, and diversity of the T cell receptor repertoire of infiltrating lymphocytes. The effector function of lymphocytes recovered from the lesions will be determined in vitro in tests of cytolytic activity against tumor targets, and the ability to secrete pro and/or anti-inflammatory cytokines will be measured by ELISA/ELISPOT. The immunotherapeutic potential of this approach will ultimately be evaluated through tumor progression and animal survival curves in the syngeneic models. (AU)