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Cytomegalovirus (CMV) is one of the most common and relevant opportunistic pathogens in immunocompromised individuals such as kidney transplant recipients (KTRs). The exact mechanisms underlying the disability of cytotoxic T cells to provide sufficient protection against CMV in immunosuppressed individuals have not been identified yet. Here, we performed in-depth metabolic profiling of CMV-specific CD8+ T cells in immunocompromised patients and show the development of metabolic dysregulation at the transcriptional, protein, and functional level of CMV-specific CD8+ T cells in KTRs with non-controlled CMV infection. These dysregulations comprise impaired glycolysis and increased mitochondrial stress, which is associated with an intensified expression of the nicotinamide adenine dinucleotide nucleotidase (NADase) CD38. Inhibiting NADase activity of CD38 reinvigorated the metabolism and improved cytokine production of CMV-specific CD8+ T cells. These findings were corroborated in a mouse model of CMV infection under conditions of immunosuppression. Thus, dysregulated metabolic states of CD8+ T cells could be targeted by inhibiting CD38 to reverse hypo-responsiveness in individuals who fail to control chronic viral infection.

Background: The survival of patients with cervical cancer who are treated with cisplatin in conjunction with the topoisomerase I inhibitor topotecan is enhanced when compared with patients treated with only one of these chemotherapeutics. Moreover, cisplatin-based and T cell-based immunotherapy have been shown to synergize, resulting in stronger antitumor responses. Here, we interrogated whether topotecan could further enhance the synergy of cisplatin with T cell-based cancer immunotherapy., Methods: Mice bearing human papilloma virus 16 (HPV16) E6/E7-expressing TC-1 tumors were vaccinated with HPV16 E7 long peptides and additionally received chemotherapy consisting of cisplatin and topotecan. We performed an in-depth study of this combinatorial chemoimmunotherapy on the effector function and expansion/contraction kinetics of vaccine-induced CD8 + T cells in the peripheral blood and tumor microenvironment (TME). In addition, we interrogated the particular role of chemotherapy-induced upregulation of costimulatory ligands by tumor-infiltrated myeloid cells on T cell proliferation and survival., Results: We show that E7 long peptide vaccination combined with cisplatin and topotecan, results in CD8 + T cell-dependent durable rejection of established tumors and 94% long-term survival. Although topotecan initially repressed the expansion of vaccine-induced CD8 + T cells, these cells eventually expanded vigorously, which was followed by delayed contraction. These effects associated with the induction of the proliferation marker Ki-67 and the antiapoptosis molecule Bcl-2 by intratumoral tumor-specific CD8 + T cells, which was regulated by topotecan-mediated upregulation of the costimulatory ligand CD70 on myeloid cells in the TME., Conclusions: Taken together, our data show that although treatment with cisplatin, topotecan and vaccination initially delays T cell expansion, this combinatorial therapy results eventually in a more robust T cell-mediated tumor eradication due to enhancement of costimulatory molecules in the TME., Competing Interests: Competing interests: This study has been conducted by LUMC, which holds a patent on the use of synthetic long peptides as vaccine (US 7.202.034). CJMM and SHvdB are named as inventors on this patent. Additionally, the LUMC holds a patent on the use of T cell cycle synchronization to optimize antitumor responses (No2019548). SHvdB, RA, CJMM and TCvdS are named inventors on this patent. CJMM is employed full time by ISA Pharmaceuticals, which exploits the long-peptide vaccine patent, and has been granted options on ISA Pharmaceuticals stock. SHvdB is a member of the Scientific Advisory Board and receives consultancy fees from ISA Pharmaceuticals. RA is a member of the Scientific Advisory Board of QIAGEN., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Factors that govern the complex formation of memory T cells are not completely understood. A better understanding of the development of memory T cell heterogeneity is however required to enhance vaccination and immunotherapy approaches. Here we examined the impact of pathogen- and tissue-specific cues on memory CD8 + T cell heterogeneity using high-dimensional single-cell mass cytometry and a tailored bioinformatics pipeline. We identified distinct populations of pathogen-specific CD8 + T cells that uniquely connected to a specific pathogen or associated to multiple types of acute and persistent infections. In addition, the tissue environment shaped the memory CD8 + T cell heterogeneity, albeit to a lesser extent than infection. The programming of memory CD8 + T cell differentiation during acute infection is eventually superseded by persistent infection. Thus, the plethora of distinct memory CD8 + T cell subsets that arise upon infection is dominantly sculpted by the pathogen-specific cues and further shaped by the tissue environment., Competing Interests: The authors declare no competing interests., (© 2020 The Author(s).)