Increased human T-cell leukemia virus type 1 (HTLV-1) proviral load (PVL) is a significant risk factor for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is controversy surrounding whether HTLV-1-specific cytotoxic T lymphocytes (CTLs) are beneficial or harmful to HAM/TSP patients. Recently, HTLV-1 Tax 301-309 has been identified as an immunodominant epitope restricted to HLA-A*2402. We investigated whether HLA-A*24 reduces HTLV-1 PVL and the risk of HAM/TSP using blood samples from 152 HAM/TSP patients and 155 asymptomatic HTLV-1 carriers. The allele frequency of HLA-A*24 was higher in HAM/TSP patients than in asymptomatic HTLV-1 carriers (72.4% vs. 58.7%, odds ratio 1.84), and HLA-A*24-positive patients showed a 42% reduction in HTLV-1 PVL compared to negative patients. Furthermore, the PVL negatively correlated with the frequency of Tax 301-309-specific CTLs. These findings are opposite to the effects of HLA-A*02, which reduces HTLV-1 PVL and the risk of HAM/TSP. Therefore, we compared the functions of CTLs specific to Tax 11-19 or Tax 301-309, which are immunodominant epitopes restricted to HLA-A*0201 or HLA-A*2402, respectively. The maximum responses of these CTLs were not different in the production of IFN-γ and MIP-1β or in the expression of CD107a-a marker for the degranulation of cytotoxic molecules. However, Tax 301-309-specific CTLs demonstrated 50-fold higher T-cell avidity than Tax 11-19-specific CTLs, suggesting better antigen recognition at low expression levels of the antigens. These findings suggest that HLA-A*24, which induces sensitive HTLV-1-specific CTLs, increases the risk of HAM/TSP despite reducing HTLV-1 PVL.

Monkeypox virus (MPXV) of poxviridae family causes a zoonotic disease called monkeypox (Mpox). MPXV cases have a fatality ratio ranging from 0 to 11% globally and have been more prevalent in children. There are three generations of smallpox vaccines that protect against MPXV. First and second generation of the vaccinia virus (VACV) vaccine protects MPXV. However, various adverse side effects were associated with the first and second generations of vaccines. In contrast, the Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN) replication-incompetent vaccine shows fewer adverse effects and a significant amount of neutralizing antibodies in mammalian cells. A third-generation Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN) was approved to prevent Mpox in 2019. Recently, MVA-BN-based Imvanex, Imvamune, and JYNNEOS vaccines have also been administered against MPXV. Globally, the World Health Organization (WHO) declared a global health emergency in May 2022 due to increased MPXV cases. Various computational studies have also designed a multi-epitope-based vaccine against the MPXV. In the multi-epitope-based vaccine, different epitopes like B-cell, Cytotoxic T Lymphocyte (CTL), CD8+, and CD4+ epitopes were derived from MPXV proteins. Further, these epitopes were linked with the help of various linkers to design a multi-epitope vaccine against MPXV. In summary, we have provided an overview of the current status of the vaccine against MPXV.

Multiple infections enable the recombination of different strains, which may contribute to viral diversity. How multiple infections affect the competition dynamics between the two types of strains, the wild and the immune escape mutant, remains poorly understood. This study develops a novel mathematical model that includes the two strains, two modes of viral infection, and multiple infections. For the representative double-infection case, the reproductive numbers are derived and global stabilities of equilibria are obtained via the Lyapunov direct method and theory of limiting systems. Numerical simulations indicate similar viral dynamics regardless of multiplicities of infections though the competition between the two strains would be the fiercest in the case of quadruple infections. Through sensitivity analysis, we evaluate the effect of parameters on the set-point viral loads in the presence and absence of multiple infections. The model with multiple infections predict that there exists a threshold for cytotoxic T lymphocytes (CTLs) to minimize the overall viral load. Weak or strong CTLs immune response can result in high overall viral load. If the strength of CTLs maintains at an intermediate level, the fitness cost of the mutant is likely to have a significant impact on the evolutionary dynamics of mutant viruses. We further investigate how multiple infections alter the viral dynamics during the combination antiretroviral therapy (cART). The results show that viral loads may be underestimated during cART if multiple-infection is not taken into account.

Determining the appropriate source of antigens for optimal antigen presentation to T cells is a major challenge in designing dendritic cell (DC) -based therapeutic strategies against hepatocellular carcinoma (HCC). Tumor-derived exosomes (Tex) express a wide range of tumor antigens, making them a promising source of antigens for DC vaccines. As reported, the exosomes secreted by tumor cells can inhibit the antitumor function of immune cells. In this study, we transfected hepatocellular carcinoma cells with Rab27a to enhance the yield of exosomes, which were characterized using transmission electron microscopy and Western blot analysis. We found that Tex secreted by overexpressing Rab27a Hepatocellular carcinoma cell lines pulsed DC is beneficial for the differentiation and maturation of DCs but inhibits the secretion of the IL-12 cytokine. Consequently, we developed a complementary immunotherapy approach by using Tex as an antigen loaded onto DCs, in combination with the cytokine IL-12 to induce antigen-specific cytotoxic T lymphocytes （CTLs）. The results indicated that the combination of DC-Tex and IL-12 was more effective in stimulating T lymphocyte proliferation, releasing IFN-γ， and enhancing cytotoxicity compared to using exosomes or IL-12 alone. Additionally, the inclusion of IL-12 also compensated for the reduced IL-2 secretion by DCs caused by Tex. Moreover, in a BALB/c nude mice model of hepatocellular carcinoma, CTLs induced by DC-Tex combined with IL-12 maximized the tumor-specific T-cell immune effect and suppressed tumor growth. Thus, Tex provides a novel and promising source of antigens, with cytokines compensating for the shortcomings of Tex as a tumor antigen. This work helps to clarify the role of exosomes in tumor immunotherapy and may offer a safe and effective prospective strategy for the clinical application of exosome-based cellular immunotherapy.

Immunotherapy using immune checkpoint inhibitors (ICIs) has shown superior efficacy compared with conventional chemotherapy in certain cancer types, establishing immunotherapy as the fourth standard treatment alongside surgical intervention, chemotherapy, and radiotherapy. In cancer immunotherapy employing ICIs, CD8-positive cytotoxic T lymphocytes are recognized as the primary effector cells. For effective clinical outcomes, it is essential that the targeted cancer cells express HLA class I molecules to present antigenic peptides derived from the tumor. However, cancer cells utilize various mechanisms to downregulate or lose HLA class I molecules from their surface, resulting in evasion from immune surveillance. Correlations between prognosis and the integrity of HLA class I molecules expressed by cancer cells have been consistently found across different types of cancer. This paper provides an overview of the regulatory mechanisms of HLA class I molecules and their role in cancer immunotherapy, with a particular emphasis on the significance of utilizing pathological tissues to evaluate HLA class I molecules expressed in cancer cells.

Identification of cytotoxic T lymphocyte (CTL) epitopes from tumor related antigens is a promising approach for malignant tumor immunotherapy. TC2N, a recently identified tumor associated antigen from human glioblastoma, is regarded as a promising target of tumor-specific immunotherapy. As one of the most widely used histocompatibility molecules in Chinese is HLA-A*0201, we were able to identify the TC2N peptides that are provided by this molecular type. A panel of antigenic peptides produced from TC2N were predicted by using a computer tool. The binding affinities of three peptides with the highest predicted score to the HLA-A*0201 molecule were evaluated after synthesis. In vitro and in vivo stimulation of the main T-cell response against the predicted peptides. The results demonstrated that TC2N (152-160) was able to release IFN-γ and lyse U251 cells in vitro as well as in vivo by eliciting peptide-specific CTLs. Our results indicated that peptide TC2N (152-160) (RLYGSVCDL) was a novel HLA-A2.1-restricted CTL epitope capable of inducing TC2N specific CTLs in vitro. As TC2N might qualify as a viable target for immunotherapeutic approaches for patients with GBM, we speculated that the newly identified epitope RLYGSVCDL would be of potential use in peptide-based, cancer-specific immunotherapy against GBM.

BACKGROUND: A minute fraction of patients stands to derive substantial benefits from immunotherapy, primarily attributable to immune evasion. Our objective was to formulate a predictive signature rooted in genes associated with cytotoxic T lymphocyte evasion (CERGs), with the aim of predicting outcomes and discerning immunotherapeutic response in colorectal cancer (CRC).
METHODS: 101 machine learning algorithm combinations were applied to calculate the CERGs prognostic index (CERPI) under the cross-validation framework, and patients with CRC were separated into high- and low-CERPI groups. Relationship between immune cell infiltration levels, immune-related scores, malignant phenotypes and CERPI were further analyzed. Various machine learning methods were used to identify key genes related to both patient survival and immunotherapy benefits. Expression of HOXC6, G0S2, and MX2 was evaluated and the effects of HOXC6 and G0S2 on the viability and migration of a CRC cell line were in-vitro verified.
RESULTS: The CERPI demonstrated robust prognostic efficacy in predicting the overall survival of CRC patients, establishing itself as an independent predictor of patient outcomes. The low-CERPI group exhibited elevated levels of immune cell infiltration and lower scores for tumor immune dysfunction and exclusion, indicative of a greater potential benefit from immunotherapy. Moreover, there was a positive correlation between CERPI levels and malignant tumor phenotypes, suggesting that heightened CERPI expression contributes to both the occurrence and progression of tumors. Thirteen key genes were identified, and their expression patterns were scrutinized through the analysis of single-cell datasets. Notably, HOXC6, G0S2, and MX2 exhibited upregulation in both CRC cell lines and tissues. Subsequent knockdown experiments targeting G0S2 and HOXC6 resulted in a significant suppression of CRC cell viability and migration.
CONCLUSIONS: We developed the CERPI for effectively predicting survival and response to immunotherapy in patients, and these results may provide guidance for CRC diagnosis and precise treatment.

The recognition by cytotoxic T cells (CTLs) is essential for the clearance of SARS-CoV-2 virus-infected cells. Several viral proteins have been described to be recognized by CTLs. Among them, the spike (S) protein is one of the immunogenic proteins. The S protein acts as a ligand for its receptors, and several mutants with different affinities for its cognate receptors have been reported, and certain mutations in the S protein, such as L452R and Y453F, have been found to inhibit the HLA-A24-restricted CTL response. In this study, we conducted a screening of candidate peptides derived from the S protein, specifically targeting those carrying the HLA-A24 binding motif. Among these peptides, we discovered that NF9 (NYNYLYRLF) represents an immunogenic epitope. CTL clones specific to the NF9 peptide were successfully established. These CTL clones exhibited the ability to recognize endogenously expressed NF9 peptide. Interestingly, the CTL clone demonstrated cross-reactivity with the Y453F peptide (NYNYLFRLF) but not with the L452R peptide (NYNYRYRLF). The CTL clone was able to identify the endogenously expressed Y453F mutant peptide. These findings imply that the NF9-specific CTL clone possesses the capability to recognize and respond to the Y453F mutant peptide.

The treatment of human immunodeficiency virus (HIV-1) has evolved since the establishment of combination antiretroviral therapy (ART) in the 1990s, providing HIV-infected individuals with approaches that suppress viral replication, prevent acquired immunodeficiency syndrome (AIDS) throughout their lifetime with continuous therapy, and halt HIV transmission. However, despite the success of these regimens, the global HIV epidemic persists, prompting a comprehensive exploration of potential strategies for an HIV cure. Here, we offer a consolidated overview of cell-based therapies for HIV-1, focusing on CAR-T cell approaches, gene editing, and immune modulation. Persistent challenges, including CAR-T cell susceptibility to HIV infection, stability, and viral reservoir control, underscore the need for continued research. This review synthesizes current knowledge, highlighting the potential of cellular therapies to address persistent challenges in the pursuit of an HIV cure.

Epithelial-mesenchymal transition (EMT) is a dynamic program crucial for organismal development and tissue regeneration. Unfortunately, this program is often hijacked by epithelial tumors to facilitate metastasis. Beyond its role in cancer spread, EMT increases cancer cell survival by activating stem cell programs and bypassing apoptotic programs. Importantly, the capacity of EMT to enforce tumor progression by altering the tumor cell phenotype without triggering immune responses opens the intriguing possibility of a mechanistic link between EMT-driven cancers and immune evasion. Indeed, EMT has been acknowledged as a of driver immune evasion, but the mechanisms are still evolving. Here, we review recent insights into the influence of EMT on tumor immune evasion. Specifically, we focus on the mechanistic roles of EMT in immune escape as the basis that may provide a platform for innovative therapeutic approaches in advanced tumors. We summarize promising therapeutic approaches currently in clinical trials and trending preclinical studies aimed at reinvigorating the tumor microenvironment to create immune-permissive conditions that facilitates immune-mediated tumor clearance. We anticipate that this will assist researchers and pharmaceutical companies in understanding how EMT compromises the immune response, potentially paving the way for effective cancer therapies.