Cancer immunology research最新文献

Tumor-associated antigen (TAA) vaccines are being explored as a strategy to induce antitumor immune responses. Mammaglobin-A (Mam-A) is a TAA expressed in >50% of breast cancer (BC) patients. Previously, we have shown that Mam-A DNA vaccines induce antitumor immune responses in patients with stable metastatic disease. To further evaluate the potential of the Mam-A vaccine, we initiated a phase-1b clinical trial in estrogen receptor-positive BC patients prior to surgery. Eight patients were assigned to Arm 1 (neoadjuvant endocrine therapy alone) and 17 to Arm 2 (neoadjuvant endocrine therapy plus Mam-A vaccination); the final analysis included 8 patients from Arm 1 and 13 from Arm 2. Ex vivo ELISpot analysis of peripheral blood mononuclear cells demonstrated that Mam-A vaccination induced Mam-A-specific T cells in 8/13 patients. Intracellular cytokine staining, and Mam-A-specific tetramer staining revealed that vaccine-induced Mam-A-specific T cells included both CD4+ and CD8+ polyfunctional T cells. Finally, high-throughput imaging mass cytometry identified 24 cellular meta-clusters with features of tumor, immune, stromal, and endothelial cells and revealed an increased CD8+ T-cell prevalence in the tumor after Mam-A vaccination. In particular, vaccination was associated with the infiltration of PD-1+CD8+ T cells. In addition, post-vaccination tumor samples exhibited close spatial interactions between cytotoxic CD8+ T cells (CTL) and Mam-A+ tumor cells and between CTL and antigen-experienced CD4+ T cells. Together, these results suggest that Mam-A DNA vaccination elicits both systemic and intratumoral antitumor immune responses.

Some patients undergoing immune checkpoint blockade treatment develop immune-related adverse events (irAEs) affecting multiple organs, but whether pituitary and thyroid dysfunction are prone to co-occur is unclear. A total of 1,014 patients treated at Nagoya University Hospital were prospectively assessed for pituitary and thyroid function, and HLAs were analyzed in patients with pituitary and/or thyroid irAEs. Pituitary irAE and thyroid irAE developed in 68 and 128 patients, respectively. The incidence of thyroid irAE was significantly higher in patients who developed pituitary irAE compared to those who did not [21/68 (30.9%) vs. 107/946 (11.3%), p <0.001], and the difference remained significant with tumor type and therapeutic agents used as stratified factors (Cochran-Mantel-Haenszel test, p = 0.001). The frequencies of HLA-DRB1*15:01 (12.5% vs. 7.6%, p = 0.049) and DRB1*15:02 (16.9% vs 10.6%, p = 0.025) were significantly higher in patients with pituitary irAE compared to those in a database containing Japanese subjects. The frequency of the DRB1*15:01-associated haplotype (DRB1*15:01-DQB1*06:02-DPB1*02:01) was significantly higher in patients who developed both pituitary and thyroid irAEs compared to the control (14.3% vs. 3.1%, p = 0.002), and the DRB1*15:02-associated haplotype (DRB1*15:02-DQB1*06:01-DPB1*09:01) frequency was significantly higher in patients who developed pituitary irAE but not thyroid irAE compared to the control (18.1% vs. 8.9%, p = 0.006); both findings were confirmed in the validation cohort comprising 92 patients with pituitary irAE from seven hospitals. In conclusion, pituitary and thyroid irAEs are prone to co-occur and HLA-DR15-associated haplotypes are related to this co-occurrence.

Cellular immunotherapies show remarkable efficacy against hematologic malignancies. However, applying these therapies against solid tumors is challenging. Among the obstacles are the lack of tumor-specific antigens and the immunosuppressive tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) expressing fibroblast activation protein (FAP) are key contributors to shaping this immunosuppressive landscape, yet developing effective strategies for targeting these cells remains an ongoing challenge. In this study, we describe the design, generation, and characterization of MiNK-215, an allogeneic human invariant NK T (iNKT) cell therapy in which iNKT cells were engineered to express an FAP-targeting chimeric antigen receptor (CAR) and to secrete IL15 to remodel the TME and enhance antitumor activity. MiNK-215 modulated multifunctional immune responses by enhancing T-cell responsiveness, dendritic cell activation, M1 macrophage polarization, and tumor killing. In a lung tumor mouse model, MiNK-215 depleted FAP+ CAFs, enhanced antigen-specific T-cell infiltration, and promoted durable antitumor immunity without off-target toxicity. These findings were extended to human organoid models of treatment-refractory microsatellite-stable colorectal cancer liver metastases, establishing FAP-CAR-IL15 iNKT cells as a promising strategy to overcome immunotherapy resistance in solid tumors. See related Spotlight by Albelda, p. 184.

The transition from trainee to independent investigator is one of the most challenging and formative phases of a scientific career. It requires not only scientific expertise but also the skills to lead, mentor, manage, and communicate effectively. The Arthur and Sandra Irving Cancer Immunology Symposium serves as a platform for established investigators to mentor trainees and early-career faculty as they navigate this transition to independence. Through sharing personal experiences and lessons from their own careers, senior leaders provide guidance on the scientific, professional, and personal challenges that shape a successful career in cancer immunology-emphasizing how curiosity, persistence, and a translational mindset can make a lasting real-world impact. This commentary highlights key themes, including leadership, communication, recruitment, and fundraising. Altogether, these insightful thoughts provide a framework for the next generation of cancer immunologists as they establish their independent careers as future leaders in the field.

Oncolytic viruses (OV) are thought to mediate antitumor activity by killing tumor cells and inducing antitumor immunity, but how this happens is not well understood. In this issue, Ludwig and colleagues show that PVSRIPO, an oncolytic poliovirus being developed for glioblastoma, may induce better immune and therapeutic responses when injected into both tumor and tumor-draining lymph nodes. Dual delivery may be a novel approach to optimize OV treatment and has implications for how we manage patients with solid tumors in the era of local immunotherapy. See related article by Ludwig et al., p. 228.

Tumor-draining lymph nodes are a pivotal site for antitumor T-cell priming. However, their mechanistic roles in cancer immune surveillance and immunotherapy response remain poorly defined. Intratumor (IT) virotherapy generates antitumor T-cell immunity through multifaceted engagement of innate antiviral inflammation. In this study, we identify type-I interferon (IFNI) signaling in glioma-draining cervical lymph nodes as a mediator of IT polio virotherapy. Transient IFNI signaling after IT administration was rescued by cervical perilymphatic infusion (CPLI) virotherapy, targeting cervical lymph nodes directly. Dual-site (IT plus CPLI) virotherapy induced profound inflammatory reprogramming of cervical lymph nodes, enhanced viral RNA replication and IFNI signaling in dendritic cells and high endothelial venules, augmented antiglioma efficacy in mice, and was associated with T-cell activation in patients with recurrent glioblastoma. A phase II clinical trial of IT plus CPLI polio virotherapy is ongoing (NCT06177964). This study implicates the lymphatic system as a virotherapy target and demonstrates that CPLI virotherapy has the potential to complement brain tumor immunotherapy. See related Spotlight by Kaufman, p. 182.

Tissue-resident memory T (TRM) cells stably occupy tissues and contribute to immunosurveillance, where they are associated with favorable survival outcomes in solid tumors. Although TRM cells have been observed in lymph nodes, their phenotype and prognostic significance in diffuse large B-cell lymphoma (DLBCL) remains uncharacterized. In this study, CD103+ T cells were quantified in DLBCL samples by immunofluorescence staining of tissue biopsies and flow cytometry of cell disaggregates and linked with clinical outcomes. Across two patient cohorts, CD103+ T cells were identified in both nodal and extranodal DLBCL, and higher CD103+ T-cell levels correlated with superior clinical outcomes. Single-cell RNA sequencing revealed ITGAE-expressing T cells in both malignant and reactive lymph node samples. However, transcriptional profiles differed as a canonical TRM population was exclusively observed in the malignant setting. This TRM cluster was enriched for genes associated with cytotoxicity and activation and was validated in an external cellular indexing of transcriptomes and epitopes by sequencing (CITEseq) dataset. Flow cytometry additionally confirmed protein expression of TRM markers (CXCR6, CD39, and PD-1) on CD69+CD103+ T cells. We assessed functional activity in coculture experiments of CD103+ versus CD103- T cells with autologous CD20+ B cells, in which CD103+ T cells displayed enhanced killing. CD103+ TRM cells in DLBCL represent a prognostically favorable population with an activated/cytotoxic T-cell phenotype.

Immune checkpoint blockade (ICB) has improved outcomes for patients with several types of cancer. However, only a minority of patients with triple-negative breast cancer (TNBC) derive benefits, and the underlying mechanisms remain largely unknown. In this study, we identified family with sequence similarity 135 member B (FAM135B) as a regulator of antitumor immunity in TNBC. Single-cell sequencing data and functional assays demonstrated the critical role of FAM135B in activating cytotoxic T cells and improving the efficacy of ICB treatment by stimulating the STING pathway. Specifically, we found that FAM135B interacts with IFI16, inhibiting its ubiquitination and proteasomal degradation by competitively blocking its binding to the E3 ligase TRIM21. This initiated IFI16-dependent STING signaling, which ultimately led to increased cytotoxic T-cell activity. Deubiquitination of IFI16 at lysine 143 and lysine 561 was crucial for FAM135B-mediated activation of the STING pathway. These findings reveal that FAM135B regulates the IFI16-dependent STING pathway and subsequent immune activation. FAM135B may represent a potential predictor of ICB therapeutic responses for patients with TNBC.

Effective antitumor immunity ultimately depends on the priming and activation of tumor-specific cytotoxic CD8+ T cells; however, the role of intratumoral cell-cell immune interactions remains incompletely understood. Recent work has revealed that the temporospatial co-localization of dendritic cells (DC), T helper (Th) cells, and cytotoxic T lymphocytes (CTL) within the tumor immune microenvironment following immune checkpoint blockade correlates with clinical response. In this study, we report the integration of more than 1 million spatially resolved single-cell profiles across six spatial proteomic and transcriptomic assays, which demonstrated that DC:Th:CTL three-cell-type clusters were common even in immunotherapy-naïve and highly desmoplastic tumors, such as fibrolamellar carcinoma and pancreatic ductal adenocarcinoma. We found that these immune triads were enriched for functionally important type 1 conventional DC, mature DCs enriched in immunoregulatory molecules, CXCL13+ Th, and GZMK+ effector CTL phenotypes. Subsequent multiplex immunofluorescence imaging of more than 450 primary pancreatic ductal adenocarcinoma tumors showed that the density of antigen-presenting cell:Th:CTL three-cell-type clusters was correlated with intratumoral T-cell clonal expansion and improved overall survival. These findings suggest that DC:Th:CTL triads are conserved across solid tumors and highlight the importance of intratumoral spatial niches in mediating endogenous antitumor immunity.