Concept: Cytotoxic T cell
Cervical cancer is a major cause of cancer death in females worldwide. Cervical cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are resistant to conventional radiotherapy and chemotherapy, and CSCs/CICs are thought to be responsible for recurrence. Eradication of CSCs/CICs is thus essential to cure cervical cancer. In this study, we isolated cervical CSCs/CICs by sphere culture, and we identified a cancer testis (CT) antigen, CTCFL/BORIS, that is expressed in cervical CSCs/CICs. BORIS has 23 mRNA isoform variants classified by 6 subfamilies (sfs), and they encode 17 different BORIS peptides. BORIS sf1 and sf4 are expressed in both CSCs/CICs and non-CSCs/CICs, whereas BORIS sf6 is expressed only in CSCs/CICs. Overexpression of BORIS sf6 in cervical cancer cells increased sphere formation and tumor-initiating ability compared with those in control cells, whereas overexpression of BORIS sf1 and BORIS sf4 resulted in only slight increases. Thus, BORIS sf6 is a cervical CSC/CIC-specific subfamily and has a role in the maintenance of cervical CSCs/CICs. BORIS sf6 contains a specific c-terminal domain (C34), and we identified a human leukocyte antigen (HLA)-A2-restricted antigenic peptide, BORIS C34_24(9) encoded by BORIS sf6. A BORIS C34_24(9)-specific cytotoxic T cell (CTL) clone showed cytotoxicity for BORIS sf6-overexpressing cervical cancer cells. Furthermore, the CTL clone significantly suppressed sphere formation of CaSki cells. Taken together, the results indicate that the CT antigen BORIS sf6 is specifically expressed in cervical CSCs/CICs, that BORIS sf6 has a role in the maintenance of CSCs/CICs, and that BORIS C34_24(9) peptide is a promising candidate for cervical CSC/CIC-targeting immunotherapy.
The efficacious delivery of antigens to antigen-presenting cells (APCs), in particular to dendritic cells (DCs), and their subsequent activation remains a significant challenge in the development of effective vaccines. This study highlights the potential of dissolving microneedle arrays laden with nano-encapsulated antigen to increase vaccine immunogenicity by targeting antigen specifically to contiguous DCs networks within the skin. Following in situ uptake, skin resident DCs were able to deliver antigen encapsulated poly-D-L-lactide-co-glycolide (PGLA) nanoparticles to cutaneous draining lymph nodes where they subsequently induced significant expansion of antigen-specific T cells. Moreover, we show that antigen encapsulated nanoparticle vaccination via microneedles generated robust antigen specific cellular immune responses in mice. This approach provided complete protection in vivo against both the development of antigen-expressing B16 melanoma tumours and a murine model of para-influenza, through the activation of antigen-specific cytotoxic CD8+ T cells that resulted in efficient clearance of tumours and virus, respectively. In addition, we show promising findings that nano-encapsulation facilitates antigen retention into skin layers and provides antigen stability in microneedles. Therefore, the use of biodegradable polymeric nanoparticles for selective targeting of antigen to skin DCs subsets through dissolvable MNs provides a promising technology for improved vaccination efficacy, compliance and coverage.
The upregulation of immune checkpoint molecules, such as programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte antigen 4 (CTLA4), on immune cells occurs during acute infections, such as malaria, as well as during chronic persistent viral infections, including HIV and hepatitis B virus. These pathways are important for preventing immune-driven pathology but can also limit immune-mediated clearance of the infection. The recent success of immune checkpoint blockade in cancer therapy suggests that targeting these pathways would also be effective for preventing and treating a range of infectious diseases. Here, we review our current understanding of immune checkpoint pathways in the pathogenesis of infectious diseases and discuss the potential for therapeutically targeting these pathways in this setting.
Genetic studies have shown the association of Parkinson’s disease with alleles of the major histocompatibility complex. Here we show that a defined set of peptides that are derived from α-synuclein, a protein aggregated in Parkinson’s disease, act as antigenic epitopes displayed by these alleles and drive helper and cytotoxic T cell responses in patients with Parkinson’s disease. These responses may explain the association of Parkinson’s disease with specific major histocompatibility complex alleles.
BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Published about 7 years ago
PURPOSE: To evaluate the effects BRAF inhibition on the tumor microenvironment in patients with metastatic melanoma. EXPERIMENTAL DESIGN: Thirty-five biopsies were collected from 16 patients with metastatic melanoma pretreatment (day 0) and at 10-14 days after initiation of treatment with either BRAF inhibitor alone (vemurafenib) or BRAF + MEK inhibition (dabrafenib + trametinib), and were also taken at time of progression. Biopsies were analyzed for melanoma antigens, T cell markers, and immunomodulatory cytokines. RESULTS: Treatment with either BRAF inhibitor alone or BRAF + MEK inhibitor was associated with an increased expression of melanoma antigens and an increase in CD8+ T cell infiltrate. This was also associated with a decrease in immunosuppressive cytokines (IL-6 & IL-8) and an increase in markers of T cell cytotoxicity. Interestingly, expression of exhaustion markers TIM-3 and PD1 and the immunosuppressive ligand PDL1 were increased on treatment. A decrease in melanoma antigen expression and CD8 T cell infiltrate was noted at time of progression on BRAF inhibitor alone, and was reversed with combined BRAF and MEK inhibition. CONCLUSIONS: Together, this data suggests that treatment with BRAF inhibition enhances melanoma antigen expression and facilitates T cell cytotoxicity and a more favorable tumor microenvironment, providing support for potential synergy of BRAF-targeted therapy and immunotherapy. Interestingly, markers of T cell exhaustion and the immunosuppressive ligand PDL1 are also increased with BRAF inhibition, further implying that immune checkpoint blockade may be critical in augmenting responses to BRAF-targeted therapy in patients with melanoma.
Lymphomatoid papulosis (LyP) belongs to the spectrum of primary cutaneous CD30-positive lymphoproliferative disorders. Clinically, LyP is characterized by a variable number of self-healing papulo-nodular lesions, with the typical waxing and waning course. Histologically, 4 types (A, B, C, and D) have been delineated. Angioinvasive growth and large ulcers are rare findings in LyP and simulate aggressive lymphoma. We retrospectively analyzed the clinicopathologic and molecular features of angioinvasive LyP in a series of 16 patients. This new form of LyP is characterized by oligolesional papules that rapidly ulcerate and evolve into large necrotic eschar-like lesions with a diameter of 1 to 4 cm and an angiocentric and angiodestructive infiltrate of small-sized to medium-sized atypical lymphocytes expressing CD30 and frequently CD8. As in other forms of LyP, the lesions underwent spontaneous regression after a few weeks. Recurrences were common, but the prognosis was excellent with no extracutaneous spread or disease-related deaths. Complete remission occurred in 9 of 16 patients (56%). This LyP variant should be distinguished from aggressive forms of angiocentric and angiodestructive and cytotoxic T-cell lymphomas. We propose the term LyP type E for this clinically and histologically unusual variant.
Inherited defects of granule-dependent cytotoxicity lead to the life-threatening immune disorder hemophagocytic lymphohistiocytosis (HLH), characterized by uncontrolled CD8 T cell and macrophage activation. In a cohort of HLH patients with genetic abnormalities expected to result in the complete absence of perforin, Rab27a or syntaxin-11, we found that disease severity as determined by age at HLH onset differed significantly, with a severity gradient from perforin (early onset) > Rab27a > syntaxin-11 (late onset). In parallel, we have generated a syntaxin-11-deficient (Stx11-/-) murine model that faithfully reproduced the manifestations of HLH following LCMV infection. Stx11-/- murine lymphocytes exhibited a degranulation defect that could be rescued by expression of human syntaxin-11 but not expression of a C-terminal-truncated mutant. Comparison of the characteristics of LCMV infection-induced HLH in the murine counterparts of the three human conditions revealed a similar gradient in the phenotypic severity of HLH manifestations. Strikingly, the severity of HLH was not correlated with the LCMV load and not fully with differences in the intensity of cytotoxic activity. Capacity of antigen presentation differed in vivo between Rab27a- and Syntaxin-11- deficient mutants. Our data indicate that cytotoxic effectors may have other immune regulatory roles in addition to their role in controlling viral replication.
Rasmussen encephalitis (RE) is characterized by unihemispheric inflammation, progressive neurologic deficits, and intractable seizures. Inflammatory lesions consist of oligoclonally expanded cytotoxic CD8+ T cells attacking neurons and astrocytes.(1) Immunotherapies may slow down tissue and function loss, whereas convincing effects on seizure activity have rarely been reported.(2) Functional hemispherectomy (HE) is highly effective for elimination of seizures but can only be offered if no indispensable function resides in the affected hemisphere.(1) We present a patient with such an HE contraindication who was treated with natalizumab, a blocker of T-cell entry into the CNS.
Human herpesvirus 6 (HHV-6) is prevalent in healthy persons, causes disease in immunosuppressed carriers, and may be involved in autoimmune disease. Cytotoxic CD8 T cells are probably important for effective control of infection. However, the HHV-6-specific CD8 T cell repertoire is largely uncharacterized. Therefore, we undertook a virus-wide analysis of CD8 T cell responses to HHV-6. We used a simple anchor motif-based algorithm (SAMBA) to identify 299 epitope candidates potentially presented by the HLA class I molecule B*08:01. Candidates were found in 77 of 98 unique HHV-6B proteins. From peptide-expanded T cell lines, we obtained CD8 T cell clones against 20 candidates. We tested whether T cell clones recognized HHV-6-infected cells. This was the case for 16 epitopes derived from 12 proteins from all phases of the viral replication cycle. Epitopes were enriched in certain amino acids flanking the peptide. Ex vivo analysis of eight healthy donors with HLA-peptide multimers showed that the strongest responses were directed against an epitope from IE-2, with a median frequency of 0.09% of CD8 T cells. Reconstitution of T cells specific for this and other HHV-6 epitopes was also observed after allogeneic hematopoietic stem cell transplantation. We conclude that HHV-6 induces CD8 T cell responses against multiple antigens of diverse functional classes. Most antigens against which CD8 T cells can be raised are presented by infected cells. Ex vivo multimer staining can directly identify HHV-6-specific T cells. These results will advance development of immune monitoring, adoptive T cell therapy, and vaccines.
HIV is adept at avoiding naturally generated T cell responses; therefore, there is a need to develop HIV-specific T cells with greater potency for use in HIV cure strategies. Starting with a CD4-based chimeric antigen receptor (CAR) that was previously used without toxicity in clinical trials, we optimized the vector backbone, promoter, HIV targeting moiety, and transmembrane and signaling domains to determine which components augmented the ability of T cells to control HIV replication. This re-engineered CAR was at least 50-fold more potent in vitro at controlling HIV replication than the original CD4 CAR, or a TCR-based approach, and substantially better than broadly neutralizing antibody-based CARs. A humanized mouse model of HIV infection demonstrated that T cells expressing optimized CARs were superior at expanding in response to antigen, protecting CD4 T cells from infection, and reducing viral loads compared to T cells expressing the original, clinical trial CAR. Moreover, in a humanized mouse model of HIV treatment, CD4 CAR T cells containing the 4-1BB costimulatory domain controlled HIV spread after ART removal better than analogous CAR T cells containing the CD28 costimulatory domain. Together, these data indicate that potent HIV-specific T cells can be generated using improved CAR design and that CAR T cells could be important components of an HIV cure strategy.