Tumor lysate-pulsed dendritic cells can elicit an effective antitumor immune response during early lymphoid recovery

Abstract

Dendritic cells (DC) can serve to immunize the newborn immune system to foreign antigen. In a lymphopenic environment, naive T cells undergoing homeostasis-driven proliferation can acquire increased sensitivity to antigen stimulation. Here, we evaluated the capacity of DC to effectively prime the host immune system to elicit antitumor effects in the setting of early lymphoid reconstitution after bone marrow transplantation (BMT). Indeed, bone marrowderived, cytokine-driven DC pulsed with whole tumor lysates (TP-DC) could, early on, prime a specific and long-lasting antitumor immune response, which mediated the rejection of a lethal challenge of a weakly immunogenic breast tumor. In the therapeutic setting, TP-DC could also inhibit the growth of preexisting breast tumor metastases by repetitive immunizations initiated early after BMT. Spleen T cells obtained from mice immunized with TP-DC early after BMT showed a substantial increase in tumor-specific IFN-␥ production. Our findings demonstrate that it is possible to promote effective antitumor immunity in a defined lymphopenic environment through DC-based immunization.

γδ T Cell Homeostasis Is Controlled by IL-7 and IL-15 Together with Subset-Specific Factors

“…Considering that, during homeostatic expansion, T cell clonotypes with increased affinity for highly represented ligands have a selective advantage (32)(33)(34) and acquire a preactivated phenotype (9), it is conceivable that homeostatic proliferation is a mechanism that evolved, in part, to allow a rapid resetting of the lymphocyte repertoire for faster and more efficient immune responses. In support of this possibility, we (35) and others (36,37) have shown that homeostatic expansion concurrent with immunization generates T cell populations enriched for CD8 ϩ effectors with enhanced antitumor activities. Here, we report that ␥␦ T cells acquire several activation markers during homeostatic expansion, but whether this principle can be used to more efficiently exploit the anti-tumor potential of these cells remains to be investigated.…”

Increased intensity lymphodepletion and adoptive immunotherapy—how far can we go?

“…56 In another model, DCs pulsed with breast tumor lysate were more effective at producing a response when administered to lymphopenic mice with a homeostatically expanding T-cell population. 57 The clinical relevance of this phenomenon was recently demonstrated in a randomized clinical trial in which high-dose chemotherapy and autologous stem-cell transplantation caused rapid and effective reconstitution of specific antimicrobial immunity after the early infusion of in vivo primed and in vitro expanded T cells. 58…”

Intravenously usable fully serotype 3 oncolytic adenovirus coding for CD40L as an enabler of dendritic cell therapy

“…29 Clinical trials of DCs-based vaccines have been applied for cancers such as renal, prostate cancer, lymphoma and melanoma. [30][31][32][33] However, clinical outcomes have been variable. Less than impressive results have been attributed to the often significant dysregulation and impairment of the transferred DCs in the immunosuppressive tumor microenvironment (TME).…”