Biology subjects

Neskey, D. M.

Publications and source records attributed to Neskey, D. M..

3 recordsLinked to original sources

bioRxiv2022

Stress-Mediated Attenuation of Translation Undermines T Cell Tumor Control

Protein synthesis enables cell growth and survival, but the molecular mechanisms through which T cells suppress or maintain protein translation in the stress of solid tumors are unknown. Using mouse models and human tumors we demonstrate that protein translation in T cells is repressed by the solid tumor microenvironment (TME) due to activation of the unfolded protein response (UPR) via phosphorylation of the subunit of eukaryotic translation initiation factor 2 (p-eIF2). Given that acute glucose deprivation in T cells exacerbated p-eIF2, we show that metabolic reprogramming toward glycolytic independence allays the UPR and p-eIF2, enabling sustained protein translation in T cells in TME stress. UPR mitigation was associated with enhanced degradation of proteins in antitumor T cells, as proteasome inhibition resulted in eIF2 phosphorylation, attenuation of translation, and loss of antitumor efficacy. In contrast, proteasome stimulation relieved translation inhibition, inducing robust T cell tumor control, offering a new therapeutic avenue to fuel the efficacy of tumor immunotherapy.

immunology↗

bioRxiv2021

B cells imprint adoptively transferred CD8+ T cells with enhanced tumor immunity

Here we report a novel strategy to reverse the tolerant state of adoptively transferred CD8+ T cells against melanoma through ex vivo expansion with the TLR9 agonist CpG. T cells generated in the presence of CpG display potent anti-tumor efficacy without in vivo co-administration of high dose IL-2 or vaccination, which are classically required for effective treatment of solid tumors using adoptive cell therapies. CD8+ T cells adopt a unique proteomic signature and are characterized by an IL-2RhighICOShighCD39low phenotype after CpG-mediated expansion. Surprisingly, we found that the presence of B cells, in the culture, was essential for imprinting CD8+ T cells with this phenotype and moreover purified B cells were sufficient to mediate the CpG-associated changes in T cells. These findings reveal a vital role for B cells in the generation of effective antitumor CD8+ T cells and have immediate implications for profoundly improving immunotherapy for patients. SUMMARY STATEMENTThe TLR9 agonist CpG allows B cells to license adoptively transferred CD8+ T cells with potent tumor immunity. These licensed T cells have a unique proteomic signature, are marked by low CD39 and high ICOS and IL-2R expression, and engraft robustly in vivo.

immunology↗

bioRxiv2021

Modeling ex vivo tumor-infiltrating lymphocyte expansion from established solid malignancies

Adoptive transfer of tumor-infiltrating lymphocytes (TIL) elicits the regression of metastatic malignancies, yet a low proportion of patients achieve complete durable responses. The high incidence of relapse in these patients highlights the need to better understand mechanisms of tumor escape from T cell control. While melanoma has provided the foundation for developing TIL therapy, much less is known about TIL efficacy and relapse in other malignancies. We sought to investigate TIL characteristics in mouse tumors which have not been studied in this setting. Here, we expanded murine TIL ex vivo in IL-2 from fragments of multiple tumor models, including oral cavity cancer models of varying immunogenicity. Additionally, TIL was expanded from pmel-1 mice bearing B16 melanoma, yielding an enriched population of tumor-infiltrating TCR transgenic T cells. Murine TILs are similar to human TIL in that they express high levels of inhibitory receptors (PD-1, Tim-3, etc.) and can be expanded ex vivo in IL-2 extensively. Of clinical relevance, we draw parallels between murine and patient TIL, evaluating relationships between PD-1, Lag-3, and Tim-3 on TILs from a cohort of oral cavity cancer patients. This platform can be used by labs even in the absence of clinical specimens or clean cell facilities and will be important to more broadly understand TIL phenotypes across many different malignancies.

immunology↗