Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling

Abstract

Lymphodepletion with total body irradiation (TBI) increases the efficacy of adoptively transferred tumor-specific CD8 + T cells by depleting inhibitory lymphocytes and increasing homeostatic cytokine levels. We found that TBI augmented the function of adoptively transferred CD8 + T cells in mice genetically deficient in all lymphocytes, indicating the existence of another TBI mechanism of action. Additional investigation revealed commensal gut microflora in the mesenteric lymph nodes and elevated LPS levels in the sera of irradiated mice. These findings correlated with increased dendritic cell activation and heightened levels of systemic inflammatory cytokines. Reduction of host microflora using antibiotics, neutralization of serum LPS using polymyxin B, or removal of LPS signaling components using mice genetically deficient in CD14 and TLR4 reduced the beneficial effects of TBI on tumor regression. Conversely, administration of microbial ligand-containing serum or ultrapure LPS from irradiated animals to nonirradiated antibody-lymphodepleted mice enhanced CD8 + T cell activation and improved tumor regression. Administration of ultrapure LPS to irradiated animals further enhanced the number and function of the adoptively transferred cells, leading to long-term cure of mice with large B16F10 tumors and enhanced autoimmune vitiligo. Thus, disruption of the homeostatic balance between the host and microbes can enhance cell-based tumor immunotherapy.

Ineffective Vaccination against Solid Tumors Can Be Enhanced by Hematopoietic Cell Transplantation

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Th17 Cells in Cancer: The Ultimate Identity Crisis

“…Given this new finding, two mechanisms can be targeted to reduce tumor growth by ETBF: one, gut microbes can be therapeutically targeted with antibiotics and two, the long-term activation of Stat3 can be inhibited to decrease a Th17 immune response. Interestingly, however, gut microbes perturbed by lymphodepletion/chemotherapy, a phenomenon called microbial translocation, improve adoptive CD8 + T cell immunotherapies for melanoma (62). Yet, how the induction of Th17 cells by microbial translocation impacts cell-based therapies for various cancers remains unknown and will be important for creating future treatments.…”

Suppressors of cytokine signaling (SOCS) in T cell differentiation, maturation, and function

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