Heat shock proteins (HSPs) are highly conserved molecular chaperones with divergent roles in various cellular processes. The HSPs are classified according to their molecular size as HSP27, HSP40, HSP60, HSP70, and HSP90. The HSPs prevent nonspecific cellular aggregation of proteins by maintaining their native folding energetics. The disruption of this vital cellular process, driven by the aberrant expression of HSPs, is implicated in the progression of several different carcinomas. Many HSPs are also actively involved in promoting the proliferation and differentiation of tumor cells, contributing to their metastatic phenotype. Upregulation of these HSPs is associated with the poor outcome of anticancer therapy in clinical settings. On the other hand, these highly expressed HSPs may be exploited as viable immunotherapeutic targets for different types of cancers. This review discusses recent advances and perspectives on the research of HSP-based cancer immunotherapy.

We report here that nucleus accumbens–associated protein-1 (NAC1), a nuclear factor of the Broad-complex, Tramtrack, Bric-a-brac/poxvirus and zinc finger (BTB/POZ) gene family, is a negative regulator of FoxP3 in regulatory T cells (T _regs ) and a critical determinant of immune tolerance. Phenotypically, NAC1 ^−/− mice showed substantial tolerance to the induction of autoimmunity and generated a larger amount of CD4 ⁺ T _regs that exhibit a higher metabolic profile and immune-suppressive activity, increased acetylation and expression of FoxP3, and slower turnover of this transcription factor. Treatment of T _regs with the proinflammatory cytokines interleukin-1β or tumor necrosis factor–α induced a robust up-regulation of NAC1 but evident down-regulation of FoxP3 as well as the acetylated FoxP3. These findings imply that NAC1 acts as a trigger of the immune response through destabilization of T _regs and suppression of tolerance induction, and targeting of NAC1 warrants further exploration as a potential tolerogenic strategy for treatment of autoimmune disorders.

EEF-2K has important roles in stress responses and cellular metabolism. We report here a previously unappreciated but critical role of eEF-2K in regulating the fate and cytocidal activity of CD8 ⁺ T cells. CD8 ⁺ T cells from eEF-2K KO mice were more proliferative but had lower survival than their wild-type counterparts after their activation, followed by occurrence of premature senescence and exhaustion. eEF-2K KO CD8 ⁺ T cells were more metabolically active and showed hyperactivation of the Akt-mTOR-S6K pathway. Loss of eEF-2K substantially impaired the activity of CD8 ⁺ T cells. Furthermore, the antitumor efficacy and tumor infiltration of the CAR-CD8 ⁺ T cells lacking eEF-2K were notably reduced as compared to the control CAR-CD8 ⁺ T cells. Thus, eEF-2K is critically required for sustaining the viability and function of cytotoxic CD8 ⁺ T cells, and therapeutic augmentation of this kinase may be exploited as a novel approach to reinforcing CAR-T therapy against cancer.

Nucleus accumbens-associated protein 1 (NAC1) is a transcription co-factor that has been shown to possess multiple roles in stem cell and cancer biology. However, little is known about its roles in regulation of the immune system. In the current study, we observed that expression of NAC1 impacted the survival of CD8⁺ T cells in vitro. NAC1^−/− CD8⁺ T cells displayed lower metabolism, including reduced glycolysis and oxidative phosphorylation. In vivo, compared with wild-type (WT) mice, NAC1^−/− mice produced a lower response to vaccinia virus (VACV) infection, and viral antigen (Ag)-specific CD8⁺ T cells decreased more slowly. Additionally, we observed that the NAC1^−/− mice demonstrated a stronger memory formation of viral Ag-specific CD8⁺ T cells post-viral infection. Mechanically, we identified that compared with WT CD8⁺ T cells, the Interferon Regulatory Factor 4 (IRF4), a key transcription factor in T cell development, was highly expressed in NAC1^−/− CD8⁺ T cells, insinuating that IRF4 could be a critical regulatory target of NAC1 in the memory formation of CD8⁺ T cells. Our results indicate that NAC1 restrains the memory formation of CD8⁺ T cells by modulating IRF4, and targeting NAC1 may be exploited as a new approach to boosting CD8⁺ T cell memory.

For the past three years, COVID-19 has become an increasing global health issue. Adaptive immune cells, especially T cells, have been extensively investigated in regard to SARS-CoV-2 infection. However, human health and T cell responses are also impacted by many other pathogens and chronic diseases. We have summarized T cell performance during SARS-CoV-2 coinfection with other viruses, bacteria, and parasites. Furthermore, we distinguished if those altered T cell statuses under coinfection would affect their clinical outcomes, such as symptom severity and hospitalization demand. T cell alteration in diabetes, asthma, and hypertension patients with SARS-CoV-2 infection was also investigated in our study. We have summarized whether changes in T cell response influence the clinical outcome during comorbidities.

The viral antigen (Ag)-specific CD8+ cytotoxic T lymphocytes (CTLs) derived from pluripotent stem cells (PSCs), i.e., PSC-CTLs, have the ability to suppress the human immunodeficiency virus (HIV) infection. After adoptive transfer, PSC-CTLs can infiltrate into the local tissues to suppress HIV replication. Nevertheless, the mechanisms by which the viral Ag-specific PSC-CTLs elicit the antiviral response remain to be fully elucidated. In this study, we generated the functional HIV-1 Gag epitope SL9-specific CTLs from the induced PSC (iPSCs), i.e., iPSC-CTLs, and investigated the suppression of SL9-specific iPSC-CTLs on viral replication and the protection of CD4+ T cells. A chimeric HIV-1, i.e., EcoHIV, was used to produce HIV replication in mice. We show that adoptive transfer of SL9-specific iPSC-CTLs greatly suppressed EcoHIV replication in the peritoneal macrophages and spleen in the animal model. Furthermore, we demonstrate that the adoptive transfer significantly reduced expression of PD-1 on CD4+ T cells in the spleen and generated persistent anti-HIV memory T cells. These results indicate that stem cell-derived viral Ag-specific CTLs can robustly accumulate in the local tissues to suppress HIV replication and prevent CD4+ T cell exhaustion through reduction of PD-1 expression.