Accumulation of CD8+ T Cells in Advanced-Stage Tumors and Delay of Disease Progression following Secondary Immunization against an Immunorecessive Epitope

Abstract

Self-reactive T cells that survive the process of positive and negative selection during thymocyte development represent potential effector cells against tumors that express these same self-Ags. We have previously shown that CD8+ T lymphocytes (TCD8) specific for an immunorecessive epitope, designated epitope V, from the SV40 large T Ag (Tag) escape thymic deletion in line SV11 Tag-transgenic mice. In contrast, these mice are tolerant to the three most dominant Tag epitopes. The majority of the residual epitope V-specific TCD8 have a low avidity for the target epitope, but a prime/boost regimen can expand higher avidity clones in vivo. Whether higher avidity TCD8 targeting this epitope are affected by Tag-expressing tumors in the periphery or can be recruited for control of tumor progression remains unknown. In the current study, we determined the fate of naive TCR-transgenic TCD8 specific for Tag epitope V (TCR-V cells) following transfer into SV11 mice bearing advanced-stage choroid plexus tumors. The results indicate that TCR-V cells are rapidly triggered by the endogenous Tag and acquire effector function, but fail to accumulate within the tumors. Primary immunization enhanced TCR-V cell frequency in the periphery and promoted entry into the brain, but a subsequent booster immunization caused a dramatic accumulation of TCR-V T cells within the tumors and inhibited tumor progression. These results indicate that epitope V provides a target for CD8+ T cells against spontaneous tumors in vivo, and suggests that epitopes with similar properties can be harnessed for tumor immunotherapy.

PD-1 Blockade Promotes Epitope Spreading in Anticancer CD8+ T Cell Responses by Preventing Fratricidal Death of Subdominant Clones To Relieve Immunodomination

“…Therefore, interfering with this checkpoint pathway boosts SDD-specific T CD8 , which in turn increases the epitope breadth of the overall T CD8 response to T Ag. This finding is important because SDDs are capable of conferring protective immunity in certain conditions (54, 55). They are ‘less visible’ to the immune system and may thus escape central or peripheral tolerance mechanisms in mice (56, 57) and humans (58).…”

Combined Anti-CD40 Conditioning and Well-timed Immunization Prolongs CD8+ T Cell Accumulation and Control of Established Brain Tumors

“…B6/T116A1 (B6/V-only Tag) cells express a Tag variant in which epitopes I (residues 207-215) and II/III (residues 223-231) are deleted and epitope IV is inactivated by alanine substitution of residues 406, 408, and 411, but in which epitope V remains intact (22) and were propagated in vitro as previously described (19). Ex vivo lymphocytes were maintained in complete RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS), 100U/mL of penicillin, 100 μg/mL streptomycin, 2 mM L-glutamine, and 50 μM 2-mercaptoethanol.…”

“…Adoptive transfers were performed as described previously (19) by intravenous injection of 5×10 6 clonotypic naïve TCR-V cells per mouse. For immunization, 5×10 7 B6/V-only Tag cells were injected intraperitoneally in 0.5 mL of PBS.…”

“…We recently investigated the fate of Tag-V specific T-CD8 in tumor-bearing SV11 mice using adoptive transfer of T-cell receptor transgenic T-CD8 specific for Tag-V (TCR-V cells) (19). TCR-V cells were activated in the tumor-draining lymph nodes within hours of transfer into tumor-bearing SV11 hosts and reached peak levels of accumulation by day 4.…”

Adoptive cell therapy with CD4+ T helper 1 cells and CD8+ cytotoxic T cells enhances complete rejection of an established tumour, leading to generation of endogenous memory responses to non‐targeted tumour epitopes

“…Vaccination with tumour-associated antigens (TAAs) has been reported to lead to expansion and accumulation of CD8 + CTLs within the tumour, resulting in enhancement of tumour regression. 21, 22 Previously, we have reported that virus-like particles (VLP) derived from rabbit haemorrhagic virus (RHDV) can be used as a vaccine construct to deliver TAAs to elicit a proliferative response of antigen-specific T cells and subsequent elimination of target cells in vivo . 23 In addition, we have also shown that TAA-expressing RHDV VLP were able to inhibit tumour growth in both a therapeutic and prophylactic manner.…”