In vivo antitumor function of tumor antigen‐specific CTLs generated in the presence of OX40 co‐stimulation in vitro

Abstract

Adoptive cell transfer (ACT) is an emerging and promising cancer immunotherapy that has been improved through various approaches. Here, we described the distinctive characteristics and functions of tumor Ag-specific effector CD8 T-cells, co-cultured with a tumor-specific peptide and a stimulatory anti-OX40 antibody, before being used for ACT therapy in tumor-bearing mouse recipients. Splenic T-cells were obtained from wild-type FVB/N mice that had been injected with a HER2/neu (neu)-expressing tumor and a neu-vaccine. The cells were then incubated for 7 days in vitro with a major histocompatibility complex (MHC) class I peptide derived from neu, in the presence or absence of an agonistic anti-OX40 monoclonal antibody, before CD8 T cells were isolated for use in ACT therapy. The proliferative ability of OX40-driven tumor Ag-specific effector CD8 T-cells in vitro was less than that of non-OX40-driven tumor Ag-specific effector CD8 T-cells, but they expressed significantly more early T-cell differentiation markers, such as CD27, CD62L and CCR7, and significantly higher levels of Bcl-2, an anti-apoptotic protein. These OX40-driven tumor Ag-specific effector CD8 T-cells, when transferred into tumor-bearing recipients, demonstrated potent proliferation capability and successfully eradicated the established tumor. In addition, these cells exhibited long-term antitumor function, and appeared to be established as memory T-cells. Our findings suggest a possible in vitro approach for improving the efficacy of ACT, which is simple, requires only a small amount of modulator, and can potentially avoid several toxicities associated with co-stimulation in vivo.

Targeting LAG3/GAL-3 to overcome immunosuppression and enhance anti-tumor immune responses in multiple myeloma

“…Checkpoint blockade is a revolutionary cancer immunotherapy; however, a large proportion (70-80%) of checkpoint inhibitor-treated cancer patients do not benefit due to either intrinsic or acquired resistance [30][31][32][33]. Multiple factors contribute to checkpoint blockade resistance including a lack of antigen-specific immune responses and/ or impaired infiltration of effector T cells to tumor sites [34][35][36][37][38][39]. An important goal of our studies was to better elucidate potential mechanisms whereby immune inhibitory receptors and ligands regulate innate and adaptive immunity in MM, and specifically delineate potential mechanisms of resistance to checkpoint blockade in MM.…”

“…Specifically, checkpoint inhibitor (especially anti-LAG3) treatment significantly increased T-cell responses in BMMC/PBMC from MM patients compared with healthy donors. Along with identifying the potential functional role of checkpoint inhibitors, we also examined the impact of immune agonists such as OX40 (CD134) and GITR (CD357) to activate costimulatory molecules on effector cells and thereby enhance their immune responses [ 36 , 37 ]. In both MM patient BMMC and PBMC, immune agonist treatment enhanced immune responses and T-cell proliferation.…”

Keystone pathobionts associated with colorectal cancer promote oncogenic reprograming

“…To better understand how the Apc Min/+ model affects CTLs post-ETBF exposure, we compared the transcriptional profiles from ETBF-exposed Apc Min/+ with ETBF-exposed WT mice. We found WT ETBF-exposed CTLs upregulated genesets involved in cytotoxic T lymphocyte −mediated apoptosis of target cells, T cell receptor signaling and OX40 signaling pathway [106][107][108], suggesting that ETBF treatment under normal conditions elicits a robust CTL response, and that this is suppressed in the Apc Min/+ mice (Fisher's exact test p-values < 0.05, Bonferroni-corrected p-values < 0.05, IPA canonical pathway analysis) (Fig 4D). These results further support a model where CRC pathobionts induce T-cell dependent immunogenicity that is largely abrogated when tumors are present.…”

Keystone pathobionts associated with colorectal cancer promote oncogenic reprograming

“…To better understand how the Apc Min/+ model affects CTLs post-ETBF exposure, we compared the transcriptional profiles from ETBF-exposed Apc Min/+ with ETBF-exposed WT mice. We found WT ETBF-exposed CTLs upregulated genesets involved in cytotoxic T lymphocyte−mediated apoptosis of target cells, T cell receptor signaling and OX40 signaling pathway [106][107][108] , suggesting that ETBF treatment under normal conditions elicits a robust CTL response, and that this is suppressed in the Apc Min/+ mice (Fisher's exact test p-values < 0.05, Bonferroni-corrected p-values < 0.05, IPA canonical pathway analysis) (Figure 4D). These results further support a model where CRC pathobionts induce T-cell dependent immunogenicity that is largely abrogated when tumors are present.…”