Upregulated Wnt/β-catenin signaling is associated with increased cancer cell resistance and cancer cell-elicited immunosuppression. In non-neoplastic immune cells, upregulated Wnt/β-catenin is, however, associated with either immunosuppression or immunostimulation. Therefore, it is difficult to predict the therapeutic impact inhibitors of Wnt/β-catenin signaling will have when combined with cancer immunotherapy. Here, we evaluated the benefit(s) of the Wnt/β-catenin signaling inhibitor XAV939 in the in vitro elimination of LNCaP prostate cancer cells when cocultured with lymphocytes from patients with localized biochemically recurrent prostate cancer (BRPCa). We found that 5 µM XAV939 inhibited β-catenin translocation to the nucleus in LNCaP cells and CD4+ BRPCa lymphocytes without affecting their proliferation and viability. Preconditioning BRPCa lymphocytes with 5 µM XAV939 accelerated the elimination of LNCaP cells during the coculturing. However, during subsequent re-coculturing with fresh LNCaP cells, BRPCa lymphocytes were no longer able to eliminate LNCaP cells unless coculturing and re-coculturing were performed in the presence of 5 µM XAV939. Comparable results were obtained for PC-3 prostate cancer cells. These findings provide a rationale for combining cell-based immunotherapy of PCa with inhibitors of Wnt/β-catenin signaling.
Introduction
The COVID‐19 vaccine was designed to provide protection against infection by the severe respiratory coronavirus 2 (SARS‐CoV‐2) and coronavirus disease 2019 (COVID‐19). However, the vaccine's efficacy can be compromised in patients with immunodeficiencies or the vaccine‐induced immunoprotection suppressed by other comorbidity treatments, such as chemotherapy or immunotherapy. To enhance the protective role of the COVID‐19 vaccine, we have investigated a combination of the COVID‐19 vaccination with ex vivo enrichment and large‐scale expansion of SARS‐CoV‐2 spike glycoprotein‐reactive CD4
+
and CD8
+
T cells.
Methods
SARS‐CoV‐2‐unexposed donors were vaccinated with two doses of the BNT162b2 SARS‐CoV‐2 vaccine. The peripheral blood mononuclear cells of the vaccinated donors were cell culture‐enriched with T cells reactive to peptides derived from SARS‐CoV‐2 spike glycoprotein. The enriched cell cultures were large‐scale expanded using the rapid expansion protocol (REP) and the peptide‐reactive T cells were evaluated.
Results
We show that vaccination with the SARS‐CoV‐2 spike glycoprotein‐based mRNA COVID‐19 vaccine‐induced humoral response against SARS‐CoV‐2 spike glycoprotein in all tested healthy SARS‐CoV‐2‐unexposed donors. This humoral response was found to correlate with the ability of the donors' PBMCs to become enriched with SARS‐CoV‐2 spike glycoprotein‐reactive CD4
+
and CD8
+
T cells. Using an 11‐day REP, the enriched cell cultures were expanded nearly 1000‐fold, and the proportions of the SARS‐CoV‐2 spike glycoprotein‐reactive T cells increased.
Conclusion
These findings show for the first time that the combination of the COVID‐19 vaccination and ex vivo T cell large‐scale expansion of SARS‐CoV‐2‐reactive T cells could be a powerful tool for developing T cell‐based adoptive cellular immunotherapy of COVID‐19.
Personalized peptide vaccination is a promising immunotherapeutic approach in prostate cancer (PCa). We therefore examined whether an approach, utilizing personalized multiple peptide-mediated ex vivo enrichment with effector T cells reactive to multiple tumor-associated antigens (TAAs), could be employed as a basis for the development of T cell immunotherapy of PCa. In this study, we used the non-adherent fraction (lymphocytes) of cryopreserved peripheral blood mononuclear cells from a leukapheretic product of biochemically recurrent (BR, n = 14) and metastatic hormone-refractory (HR, n = 12) PCa patients. The lymphocytes were primed with a pool of mixed overlapping peptides derived from 6 PCa TAAs-PSA, PAP, NY-ESO-1, MAGE-A1, MAGE-A3 and MAGE-A4. After 2 weeks of culture, the cells were stimulated with the peptides and T cell reactivity determined by externalization of CD107a. No TAAs-reactive effector T cells were detected in the patient's lymphocytes after their reconstitution. However, following their priming with the TAAs-derived peptides and 2-week culturing, the lymphocytes became enriched with polyclonal TAAs-reactive effector CD8 T cells in 8 out of 14 BR and 5 out of 12 HR patients. No such reactive CD8 T cells were detected in cultured lymphocytes without the peptide priming. Stimulation of the responding cultures with peptides derived from individual TAAs revealed a unique repertoire of the reactive CD8 T cells. Our strategy revealed that the personalized multiple peptide-mediated ex vivo enrichment with multiple TAAs-reactive T cells in the PCa patient's lymphocytes is a viable approach for development of T cell immunotherapy of PCa.
CD8+ T cells protect against tumors and intracellular pathogens. The inflammatory cytokines IL-2, IL-15, and IL-7 are necessary for their expansion. However, elevated serum levels of these cytokines are often associated with cancer, poorer prognosis of cancer patients, and exhaustion of antigen-expanded CD8+ T cells. The impact of acute conditioning of antigen-expanded CD8+ T cells with these cytokines is unknown. Here, we generated antigen-expanded CD8+ T cells using dendritic cells and PC-3 cells. The cells were acutely (18–24 h) conditioned with IL-2 and either the GSK3β inhibitor TWS119, the mTORC1 inhibitor rapamycin, or the mTORC1/2 inhibitor Torin1, then their immediate and post-re-expansion (distal) cytokine responses after antigen rechallenge were evaluated. We found that acute IL-2 conditioning upregulated the immediate antigen-induced cytokine response of the tested cells. Following their re-expansion, however, the cells showed a decreased cytokine response. These IL-2 conditioning-mediated impacts were counteracted with TWS119 or rapamycin but not with Torin1. Our data revealed that the acute conditioning of antigen-expanded CD8+ T cells with IL-2 modulates the GSK3β-mTORC signaling axis. This modulation differentially affected the immediate and distal cytokine responses of the cells. The acute targeting of this signaling axis could, therefore, represent a novel strategy for the modulation of antigen-expanded CD8+ T cells.
MicroRNAs belong to a group of short non-coding RNA molecules that are involved in the regulation of gene expression at multiple levels. Their function was described two decades ago, and, since then, microRNAs have become a rapidly developing field of research. Their participation in the regulation of cellular processes, such as proliferation, apoptosis, cell growth, and migration, made microRNAs attractive for cancer research. Moreover, as a single microRNA can simultaneously target multiple molecules, microRNAs offer a unique advantage in regulating multiple cellular processes in different cell types. Many of these cell types are tumor cells and the cells of the immune system. One of the most studied microRNAs in the context of cancer and the immune system is miR-155. MiR-155 plays a role in modulating innate and adaptive immune mechanisms in distinct immune cell types. As such, miR-155 can be part of the communication between the tumor and immune cells and thus impact the process of tumor immunoediting. Several studies have already revealed its effect on antitumor immune responses, and the targeting of this molecule is increasingly implemented in cancer immunotherapy. In this review, we discuss the current knowledge of miR-155 in the regulation of antitumor immunity and the shaping of the tumor microenvironment, and the plausible implementation of miR-155 targeting in cancer therapy.
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