Journal of Immunotherapy最新文献

Although most endometrial cancer (EC) patients have a favorable prognosis, the overall survival (OS) of metastatic and recurrent EC could hardly be improved by the current chemoradiotherapy. We aimed to reveal the tumor microenvironment immune infiltration characteristics to elucidate the underlying mechanism of EC progression and guide clinical decisions. In the Cancer Genome Atlas (TCGA) cohort, Kaplan-Meier survival curves confirmed Tregs and CD8 T cells were prognosis-protective factors in OS of EC ( P <0.05). Weighted gene coexpression network analysis identified 2 gene modules closely correlated with Tregs and CD8 T-cell infiltration. We randomly split the TCGA EC cohort into the training and testing cohorts at a ratio of 7:3. An immune-related prognosis risk index (IRPRI), including NR3C1, E2F1, OTOG, TTK, PPP1R16B, and FOXP3, was established by univariate, Least Absolute Shrinkage and Selection Operator, and multivariate Cox regression with area under the curve >0.67. Distinct clinical, immune, and mutation characteristics existed between IRPRI groups by multiomics analysis. Cell proliferation and DNA damage repair-related pathways were activated, and immune-related pathways were inactivated in the IRPRI-high group. Furthermore, patients in the IRPRI-high group had lower tumor mutation burden, programmed death-ligand 1 expression, and Tumor Immune Dysfunction and Exclusion scores, indicating a poor response to immune checkpoint inhibitors therapy ( P <0.05), which was also validated in the TCGA testing cohort and independent cohorts, GSE78200, GSE115821, and GSE168204. Also, the higher mutation frequencies of BRCA1, BRCA2, and genes enrolled in homologous recombination repair in the IRPRI-low group predicted a good response to PARP inhibitors. Finally, a nomogram integrating the IRPRI group and prognosis significant clinicopathological factors for EC OS prediction was developed and validated with good discrimination and calibration.

Immune checkpoint inhibitors (ICI) are antibodies that block immune checkpoint proteins from binding with their partner proteins on cancer cells, subsequently allowing cytotoxic T-cell-associated enhancement of antitumor responses. Although ICIs have become the standard of care for various malignancies, their use is often limited by unique immune-related adverse events, including dermatologic, endocrine, inflammatory, hepatic, and gastrointestinal events. Diarrhea and colitis are common lower gastrointestinal tract immune-related adverse events, however, only a few cases have reported the association between celiac disease (CD) and ICIs. We report here a case of a 75-year-old man with new onset CD after exposure to the cytotoxic T-lymphocyte-associated antigen-4 ICI, ipilimumab. Although ICI-induced CD is relatively rare, it is essential to consider it in a genetically susceptible patient undergoing treatment with ICI. Patients with known high susceptibility to CD, such as a family history of CD, or with the ancestry of high celiac penetrance (eg, Northern Europe, North Africa, etc), dermatitis herpetiformis, or chronic bowel symptoms, we feel should have celiac panel testing before initiating ICI therapy.

Human epidermal growth factor receptor 2 (HER2) overexpression has been demonstrated in a variety of cancers. Targeted therapy with anti-HER2 monoclonal antibodies (mAbs) has been approved as a therapeutic modality. Despite the efficacy of mAbs in tumor treatment, many patients do not benefit from this therapeutic platform. Fragment crystallizable (Fc) engineering is a common approach to improve the efficacy of therapeutic mAbs. Five Fc-engineered mAbs have so far been approved by FDA. We have recently developed an anti-HER2 bispecific mAb, BiHT, constructed from variable domains of trastuzumab, and our novel humanized anti-HER2 mAb, hersintuzumab. BiHT displayed promising antitumor activity as potently as the combination of the parental mAbs. Here, we aimed to modify the Fc of BiHT to improve its therapeutic efficacy. The Fc-engineered BiHT (MBiHT) bound to recombinant HER2 and its subdomains with an affinity similar to BiHT. It also recognized native HER2 on different cell lines, inhibited their proliferation, downregulated HER2 expression, and suppressed downstream signaling pathways similar to BiHT. Compared with BiHT, MBiHT displayed enhanced antibody-dependent cellular cytotoxicity activity against various tumor cell lines. It also inhibited the growth of ovarian xenograft tumors in nude mice more potently than BiHT. Our findings suggest that MBiHT could be a potent therapeutic candidate for the treatment of HER2-overexpressing cancer types.

Therapeutic cancer vaccines including sipuleucel- T , a prostatic acid phosphatase (PAP) targeted vaccine that improves survival in metastatic castration-resistant prostate cancer (mCRPC), can produce immune responses that translate to clinical benefit. The effects of sequential checkpoint inhibitors after therapeutic vaccine on immune responses are unknown. Avelumab is an anti-programmed death ligand-1 monoclonal antibody evaluated in patients with mCRPC in the JAVELIN solid tumor phase 1 trial expansion cohort, enriched for patients with a previous therapeutic prostate cancer-targeted vaccine. mCRPC patients received intravenous avelumab 10 mg/kg every 2 weeks with imaging every 6 weeks. Peripheral blood T-cell responses to PAP and to PA2024, the peptide containing PAP utilized by the vaccine, were evaluated pre and posttreatment. Eighteen patients enrolled, and previous treatments included abiraterone or enzalutamide in 14 (78%), therapeutic cancer vaccine in 14 (78%), and chemotherapy in 4 (22%). Avelumab had a manageable safety profile. There were no sustained prostate specific antigen decreases. Of 17 patients evaluable for best overall response by RECISTv1.1, 12 had stable disease (SD) and 5 had progressive disease. Seven patients had SD for >24 weeks posttreatment. Fourteen patients had previously received therapeutic cancer vaccines. Eleven (79%) had SD as the best overall response. Of these 14 patients, 9 had previously received sipuleucel T . Analysis of antigen-specific T-cell responses pre and postavelumab treatment did not demonstrate changes in interferon-γ production or proliferation in response to PAP or PA2024. This unplanned analysis does not support the use of sequential therapeutic cancer vaccine therapy followed by programmed death ligand-1 inhibition in mCRPC.

Adoptive cell therapy with T cells expressing affinity-enhanced T-cell receptors (TCRs) is a promising treatment for solid tumors. Efforts are ongoing to further engineer these T cells to increase the depth and durability of clinical responses and broaden efficacy toward additional indications. In the present study, we investigated one such approach: T cells were transduced with a lentiviral vector to coexpress an affinity-enhanced HLA class I-restricted TCR directed against MAGE-A4 alongside a CD8α coreceptor. We hypothesized that this approach would enhance CD4 + T-cell helper and effector functions, possibly leading to a more potent antitumor response. Activation of transduced CD4 + T cells was measured by detecting CD40 ligand expression on the surface and cytokine and chemokine secretion from CD4 + T cells and dendritic cells cultured with melanoma-associated antigen A4 + tumor cells. In addition, T-cell cytotoxic activity against 3-dimensional tumor spheroids was measured. Our data demonstrated that CD4 + T cells coexpressing the TCR and CD8α coreceptor displayed enhanced responses, including CD40 ligand expression, interferon-gamma secretion, and cytotoxic activity, along with improved dendritic cell activation. Therefore, our study supports the addition of the CD8α coreceptor to HLA class I-restricted TCR-engineered T cells to enhance CD4 + T-cell functions, which may potentially improve the depth and durability of antitumor responses in patients.

Programmed cell death 1 ligand 1), programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), T-cell immunoglobulin and mucin-domain containing-3, lymphocyte activation gene-3, and T-cell immunoglobulin and ITIM domain (TIGIT) are considered major immune co-inhibitory receptors (CIRs) and the most promising immunotherapeutic targets in cancer treatment, but they are largely unexplored in upper tract urothelial carcinoma (UTUC). The aim of this Cohort Study was to provide evidence concerning expression profiles and the clinical significance of CIRs among Chinese UTUC patients. A total of 175 UTUC patients who received radical surgery in our center were included. We used immunohistochemistry to evaluate CIR expressions in tissue microarrays (TMAs). Clinicopathological characteristics and prognostic correlations of CIR proteins were retrospectively analyzed. TIGIT, T-cell immunoglobulin and mucin-domain containing-3, PD-1, CTLA-4, Programmed cell death 1 ligand 1, and lymphocyte activation gene-3 high expression was examined in 136(77.7%), 86(49.1%), 57(32.6%), 18(10.3%), 28(16.0%), and 18(10.3%) patients, respectively. Log-rank tests and Multivariate Cox analysis both implied CTLA-4 and TIGIT expression was associated with worse relapse-free survival. In conclusion, this is the largest Chinese UTUC cohort study, and we analyzed the Co-inhibitory receptor expression profiles in UTUC. We identified CTLA-4 and TIGIT expression as promising biomarkers for tumor recurrence. Furthermore, a subset of advanced UTUCs are probably immunogenic, for which single or combined immunotherapy may be potential therapeutic approaches in the future.

The high mortality of coronavirus disease 2019 is related to poor antigen presentation and lymphopenia. Cytomegalovirus and the herpes family encode a series of major histocompatibility complex (MHC)-like molecules required for targeted immune responses to achieve immune escape. In this present study, domain search results showed that many proteins of the severe acute respiratory syndrome coronavirus 2 virus had MHC-like domains, which were similar to decoys for the human immune system. MHC-like structures could bind to MHC receptors of immune cells (such as CD4 + T-cell, CD8 + T-cell, and natural killer-cell), interfering with antigen presentation. Then the oxygen free radicals generated by E protein destroyed immune cells after MHC-like of S protein could bind to them. Mutations in the MHC-like region of the viral proteins such as S promoted weaker immune resistance and more robust transmission. S 127-194 were the primary reason for the robust transmission of delta variants. The S 144-162 regulated the formation of S trimer. The mutations of RdRP: G671S and N: D63G of delta variant caused high viral load. S 62-80 of alpha, beta, lambda variants were the important factor for fast-spreading. S 616-676 and 1014-1114 were causes of high mortality for gamma variants infections. These sites were in the MHC-like structure regions.

Immunotherapy in combination with chemotherapy is the current treatment of choice for frontline programmed cell death ligand 1 (PD-L1)-positive gastric cancer. However, the best treatment strategy remains an unmet medical need for elderly or fragile patients with gastric cancer. Previous studies have revealed that PD-L1 expression, Epstein-Barr virus association, and microsatellite instability-high (MSI-H) are the potential predictive biomarkers for immunotherapy use in gastric cancer. In this study, we showed that PD-L1 expression, tumor mutation burden, and the proportion of MSI-H were significantly elevated in elderly patients with gastric cancer who were older than 70 years compared with patients younger than 70 years from analysis of The Cancer Genome Atlas gastric adenocarcinoma cohort [≥70/<70: MSI-H: 26.8%/15.0%, P =0.003; tumor mutation burden: 6.7/5.1 Mut/Mb, P =0.0004; PD-L1 mRNA: 5.6/3.9 counts per million mapped reads, P =0.005]. In our real-world study, 416 gastric cancer patients were analyzed and showed similar results (≥70/<70: MSI-H: 12.5%/6.6%, P =0.041; combined positive score ≥1: 38.1%/21.5%, P <0.001). We also evaluated 16 elderly patients with gastric cancer treated with immunotherapy and revealed an objective response of 43.8%, a median overall survival of 14.8 months, and a median progression-free survival of 7.0 months. Our research showed that a durable clinical response could be expected when treating elderly patients with gastric cancer with immunotherapy, and this approach is worth further study.

T-cell immunotherapies are promising strategies to generate T-cell responses towards tumor-derived or pathogen-derived antigens. Adoptive transfer of T cells genetically modified to express antigen receptor transgenes has shown promise for the treatment of cancer. However, the development of T-cell redirecting therapies relies on the use of primary immune cells and is hampered by the lack of easy-to-use model systems and sensitive readouts to facilitate candidate screening and development. Particularly, testing T-cell receptor (TCR)-specific responses in primary T cells and immortalized T cells is confounded by the presence of endogenous TCR expression which results in mixed alpha/beta TCR pairings and compresses assay readouts. Herein, we describe the development of a novel cell-based TCR knockout (TCR-KO) reporter assay platform for the development and characterization of T-cell redirecting therapies. CRISPR/Cas9 was used to knockout the endogenous TCR chains in Jurkat cells stably expressing a human interleukin-2 promoter-driven luciferase reporter gene to measure TCR signaling. Reintroduction of a transgenic TCR into the TCR-KO reporter cells results in robust antigen-specific reporter activation compared with parental reporter cells. The further development of CD4/CD8 double-positive and double-negative versions enabled low-avidity and high-avidity TCR screening with or without major histocompatibility complex bias. Furthermore, stable TCR-expressing reporter cells generated from TCR-KO reporter cells exhibit sufficient sensitivity to probe in vitro T-cell immunogenicity of protein and nucleic acid-based vaccines. Therefore, our data demonstrated that TCR-KO reporter cells can be a useful tool for the discovery, characterization, and deployment of T-cell immunotherapy.