Anti‐tumor T cell response and protective immunity in mice that received sublethal irradiation and immune reconstitution

Abstract

To test whether homeostasis-driven T cell proliferation in reconstituted lymphodepleted hosts would improve the therapeutic efficacy of tumor vaccines, normal mice and reconstituted lymphopenic mice (RLM; C57BL/6 mice rendered lymphopenic with sublethal totalbody irradiation and reconstituted with naive splenocytes) were used in the vaccination and challenge experiments with weakly immunogenic F10 melanoma cells. Only limited protection was observed in vaccinated normal mice (16.7%), whereas significantly greater protection was induced in vaccinated RLM (63.2%). Protective immunity in RLM depended on CD8 T cells. Following vaccination, a significant increase in the percentage of CD44 hi CD62L lo T cells was detected in the tumor vaccine-draining lymph node (TVDLN) of vaccinated RLM compared to that of vaccinated normal mice. After in vitro stimulation, effector T cells generated from TVDLN of vaccinated RLM produced more IFN-+ than T cells from vaccinated normal mice, and contained more melanoma-specific T cells, as assessed by ELISA and intracellular cytokine staining. This study suggests that vaccination of reconstituted lymphopenic hosts could elicit superior anti-tumor immunity compared to normal hosts, highlighting the potential clinical benefit of performing tumor vaccination during immune reconstitution.

High-dose chemotherapy augments the efficacy of recombinant adenovirus vaccines and improves the therapeutic outcome

“…[8][9][10]27,28 In particular, a number of studies have investigated the combination of CTX with various vaccines. [4][5][6][7]29,30 However, in most of those studies a low dose of CTX was used (single injection of 100 mg kg À1 or less) as a strategy to selectively deplete regulatory T cells.…”

“…[4][5][6][7] Although this approach may seem counterintuitive as cytotoxic therapies often result in lymphopenia, which could limit the availability of T and B lymphocytes, several recent studies have shown that lymphopenia conditions may actually increase T-cell responsiveness to cancer vaccines. [8][9][10][11] The lymphopenic environment provides more physical space as well as abundance of cytokines and growth factors to promote expansion and differentiation of lymphocytes. In fact, it has been shown that the requirements for T-cell activation under lymphopenic conditions are less stringent and naive T cells can acquire effector-like phenotype and function despite not having been primed through the conventional T-cellantigen-presenting cell interactions.…”

Interleukin-7-Dependent Expansion and Persistence of Melanoma-Specific T Cells in Lymphodepleted Mice Lead to Tumor Regression and Editing

“…The therapeutic benefit of homeostatic proliferation-induced expansion of T cells against tumor antigens was subsequently shown in an animal tumor model (4). We and others have shown that tumor rejection was enhanced by presentation of tumor antigens during homeostatic proliferation in lymphodepleted mice (5)(6)(7)(8). Conversely, homeostatic proliferation was shown to be an obstacle to the induction of transplantation tolerance and a key factor in the development of autoimmune diabetes in nonobese diabetic mice (9,10).…”

To ablate or not to ablate? HSCs in the T cell driver’s seat

“…In murine tumor models, induction of lymphopenia followed by adoptive transfer of peptide-specific T cells alone led to regression of established tumors (8). Active vaccination in combination with lymphodepletion and adoptive T cell transfer may further enhance immunity (14,15). Studies have shown that active vaccination can skew the T cell repertoire toward self or tumor-associated antigens during homeostatic proliferation (16,17).…”