Neutrophil-dependent tumor rejection and priming of tumoricidal CD8+ T cell response induced by dendritic cells overexpressing CD95L

Abstract

Overexpression of CD95 (Fas/Apo-1) ligand (CD95L) has been shown to induce T cell tolerance but also, neutrophilic inflammation and rejection of allogeneic tissue. We explored the capacity of dendritic cells (DCs) genetically engineered to overexpress CD95L to induce an antitumor response. We first found that DCs overexpressing CD95L, in addition to MHC class I-restricted OVA peptides (CD95L-OVA-DCs), induced increased antigen-specific CD8(+) T cell responses as compared with DCs overexpressing OVA peptides alone. The enhanced T cell responses were associated with improved regression of a tumor expressing OVA, allowing survival of all animals. When DCs overexpressing CD95L (CD95L-DCs) were injected with the tumor expressing OVA, in vivo tumor proliferation was strikingly inhibited. A strong cellular apoptosis and a massive neutrophilic infiltrate developed in this setting. Neutrophil depletion prevented tumor regression as well as enhanced IFN-gamma production induced by CD95L-OVA-DCs. Furthermore, the CD8(+) T cell response induced by the coadministration of tumor cells and CD95L-DCs led to rejection of a tumor implanted at a distance from the DC injection site. In summary, DCs expressing CD95L promote tumor rejection involving neutrophil-mediated innate immunity and CD8(+) T cell-dependent adaptative immune responses.

Synergistic Innate and Adaptive Immune Response to Combination Immunotherapy with Anti-Tumor Antigen Antibodies and Extended Serum Half-Life IL-2

“…In particular, the potential for strong synergistic interaction of T-cells and neutrophils has been noted in infectious and autoimmune disease (Müller et al, 2009), but has been largely unappreciated as a contributor to tumor immunotherapy (Buonocore et al, 2008). Thus, while work in the immunotherapy space has traditionally been focused on boosting only an anti-tumor T-cell or NK cell response, a more powerful approach may be to identify ways to conscript neutrophils and other innate effector cells to synergize with existing immunotherapies that stimulate T-cell activity.…”

One microenvironment does not fit all: heterogeneity beyond cancer cells

“…Cytokine gene transfer strategies in which engineered tumors overexpress cytokines induced massive recruitment of neutrophils to tumors, leading to the rejection of tumor cells and establishment of anti-tumor immunity against wild-type parental tumor [227,228]. Tumor destruction by activated neutrophils is achieved through their release of a variety of factors including ROS, membrane-perforating agents, and cytokines (e.g., TNF-α, IL-1β, and IFNs) which result in activation of cytotoxic immune cells (e.g., NK cells, CD8+ T cells) which evoke immunological memory against tumors or antibody-dependent cellular cytotoxicity (ADCC) [181].…”

The paradox of tumor-associated neutrophils: Fueling tumor growth with cytotoxic substances

“…19,34,35 These approaches have taken advantage of the fact that PMN possess toxic substances capable of killing tumor cells, and have manipulated the neutrophil to release these substances in concentrations not typically encountered within the tumor microenvironment. Thus TAN usually function against the host but possess the potential to become valuable assets if their behavior can be safely manipulated and properly controlled.…”