Cancer immunology research最新文献

Pancreatic ductal adenocarcinoma (PDA) is characterized by a myeloid-enriched microenvironment and has shown remarkable resistance to immune checkpoint blockade (e.g., anti-PD-1 and anti-CTLA-4). In this study, we sought to define the role of myeloid immunosuppression in immune resistance in PDA. We report that although depletion of CSF1R+ myeloid cells in combination with anti-PD-1 and chemotherapy triggers T-cell infiltration into PDA, it also causes compensatory remodeling of the myeloid compartment with limited tumor control. Combination therapy against multiple myeloid targets, including CSF1R, CCR2/5, and CXCR2, was insufficient to overcome treatment resistance. High-dimensional single-cell analyses performed on T-cell infiltrates in human and mouse PDA revealed upregulation of multiple immune checkpoint molecules, including PD-1, LAG-3, and CTLA-4. Combinatorial blockade of PD-1, LAG-3, and CTLA-4 along with chemotherapy and anti-CSF1R was necessary to trigger activation of peripheral CD4+ and CD8+ T cells and led to deep, durable, and complete tumor responses, with each immune checkpoint blockade agent contributing to efficacy. Our findings indicate that a comprehensive approach targeting both negative regulatory signals controlling T-cell function and the myeloid compartment will be fundamental to unveiling the potential of immunotherapy in PDA.

Overcoming the physical barriers of the tumor microenvironment remains a major obstacle for chimeric antigen receptor (CAR) T-cell therapy in solid tumors. In this issue, Van Pelt and colleagues show that engineering GD2-targeting CAR T cells to express matrix metalloproteinase 7 and osteopontin-b enhances their ability to infiltrate tumors rich in extracellular matrix. These modifications improve functionality in preclinical models without increasing off-target toxicity. The findings highlight a promising strategy to design CAR T cells with extracellular matrix-remodeling capabilities. See related article by Van Pelt et al., p. 1732.

Pancreatic ductal adenocarcinoma (PDAC) is a rapidly progressing cancer that responds poorly to immunotherapies. Intratumoral tertiary lymphoid structures (TLS) have been associated with rare long-term PDAC survivors, but the role of TLS in PDAC and their spatial relationships within the context of the broader tumor microenvironment remain unknown. In this study, we report the generation of a spatial multiomic atlas of PDAC tumors and tumor-adjacent lymph nodes from patients treated with combination neoadjuvant immunotherapies. Using machine learning-enabled hematoxylin and eosin image classification models, imaging mass cytometry, and unsupervised gene expression matrix factorization methods for spatial transcriptomics, we characterized cellular states within and adjacent to TLS spanning distinct spatial niches and pathologic responses. Unsupervised learning identified TLS-specific spatial gene expression signatures that are significantly associated with improved survival in patients with PDAC. We identified spatial features of pathologic immune responses, including intratumoral TLS-associated B-cell maturation colocalizing with IgG dissemination and extracellular matrix remodeling. Our findings offer insights into the cellular and molecular landscape of TLS in PDACs during immunotherapy treatment.

The discovery of immune checkpoints and the rapid growth of immuno-oncology have sparked efforts to utilize the immune system to treat a wide range of cancer types/subtypes. Although the major focus of immuno-oncology over the past decades has been to manipulate the adaptive immune system, recent attention has been given to manipulating the innate immune system to treat cancer and/or to enhance adaptive responses. In this study, we detailed the intracellular protein dual specificity phosphatase 11 (DUSP11) as an innate immune checkpoint in non-small cell lung cancer adenocarcinoma (LUAD). The expression of this atypical phosphatase was correlated with patient survival for multiple cancer types, and we reported here that its activity was important for the viability of lung cancer cells in vitro. Specifically, we demonstrated that DUSP11 knockdown in LUAD cells induces apoptosis and an innate immune response capable of activating other cells in vitro, and we provided evidence that these phenotypes are primarily mediated by the pattern recognition receptor, retinoic acid-inducible gene I. Finally, we showed that the expression of DUSP11 was important for tumor engraftment and growth of human LUAD in mice. Overall, these data are the first to establish DUSP11 as an immunosuppressive, pro-neoplastic, and potentially targetable protein in LUAD. In addition, our data suggest that the anticancer mechanisms induced by diminishing the activity of DUSP11 are likely to be generalizable to other cancer types such as breast and skin cancers, warranting future investigation and highlighting therapeutic potential.

Patients with Sezary syndrome (SS), the aggressive leukemic variant of cutaneous T cell lymphoma (CTCL), have few therapeutic options and a poor prognosis. We previously showed that the IL4/IL13 signaling pathway impacts SS tumorigenesis. Here, we investigated the potential therapeutic effect of REGN668 (dupilumab), a monoclonal antibody that blocks the IL4/IL13 pathway by targeting the receptors' common IL4Rα subunit. We used single-cell RNA sequencing coupled with T cell immune repertoire analysis to define the transcriptional changes and molecular mechanisms associated with REGN668 treatment in malignant and reactive T lymphocytes, as well as in monocytes and dendritic cells from the peripheral blood of SS patients. Although REGN668 induced patient-specific transcriptional changes in malignant lymphocytes, it also downregulated several pro-tumorigenic processes that were shared across patient samples, including cell division, DNA damage/repair, autophagy, and T cell signaling pathways. Ex vivo studies demonstrated that REGN668 inhibits proliferation of malignant lymphocytes more efficiently than blocking either IL4 or IL13 signaling alone. Further, dupilumab reverts the immunosuppressive phenotype of non-clonal T lymphocytes and myeloid cells in the SS tumor microenvironment, including the function of MDSCs as well as Th2 and exhaustion pathways. Our study provides new insights into SS pathogenesis and a framework for precision therapies. While case reports have raised concerns over dupilumab-induced CTCL, these appear attributable to initial misdiagnoses rather than a direct causative effect. Our findings indicate that dupilumab exerts pathway-specific effects and could contribute to a multi-pathway therapeutic approach.

Thymomas are rare thymic epithelial tumors harboring a high but variable proportion of lymphocytes without obvious function. Autoimmunity is present in one third of patients at diagnosis. Herein, we performed a phenotypic, single-cell RNA sequencing (scRNAseq), and spatial analysis of both the T cells and tumoral cells. T cells at all stages of T-cell development-from immature to mature-were present in the tumor suggesting active thymopoiesis in thymoma. However, data generated through multiple approaches suggested a maturation blockade at the double negative to double positive stage of T-cell development. In the mature T-cell compartment, the frequency of regulatory T cells was strongly decreased. The scRNAseq analysis showed that the transcriptome of tumoral Thymic Epithelial Cells (tTEC) was most similar to that of non-tumoral medullary TEC but the expression of key molecules involved in positive and negative selection was defective. Multiplexed Immunohistochemical Consecutive Staining revealed a loss of the cortex-medulla zoning in thymoma, which may be related to a decrease in the expression of T cell-targeted chemokines by tTEC. Altogether, these results suggest that the thymopoiesis present in thymoma is abnormal and may be the cause of the prevalent autoimmunity observed in this disease.

Human leukocyte antigen class I (HLA-I) is central to tumor immune recognition, but its regulatory mechanisms in cervical cancer remain poorly understood. This study aimed to elucidate the impact of HLA-I regulatory mechanisms on CD8+ T cell infiltration and identify distinct histotype-specific immune escape strategies across cervical cancer subtypes. Using 98 cervical cancer cases, including squamous cell carcinoma (SCC, n=53), adenocarcinoma (AC, n=32), gastric-type adenocarcinoma (GAS, n=5), small cell carcinoma (Small, n=4), and mixed histological types (MIX, n=4), we examined the relationship between CD8+ T cell infiltration patterns (categorized as Infiltrated, Excluded, or Absent) and HLA-I expression, HLA-A DNA methylation, and HLA-I loss of heterozygosity (LOH). CD8+ T cell infiltration patterns varied significantly by histological subtype (P<0.0001). SCC showed the highest frequency of the Infiltrated pattern (73.6%), whereas GAS and Small predominantly displayed an Absent pattern. Reduced CD8+ T cell infiltration correlated with poor survival (P<0.0001). HLA-I expression mirrored these trends, being highest in SCC and lowest in Small and GAS. HLA-A DNA methylation emerged as a key driver of HLA-I downregulation, leading to reduced CD8+ infiltration (P<0.05). In SCC, both HLA-A methylation and HLA-I LOH contributed to immune evasion; cases lacking these alterations exhibited the highest CD8+ T cell infiltration levels (P<0.01). This study identifies distinct HLA-I regulatory mechanisms in cervical cancer, highlighting HLA-A methylation-and particularly HLA-I LOH in SCC-as key drivers of immune evasion. These findings provide a foundation for developing predictive biomarkers and suggest that targeting these specific HLA-I regulatory mechanisms could enhance immunotherapy efficacy.

Tumor-specific CD8+ T cells in blood appear to be important for and predictive of response to anti-PD-1 therapies. However, as most tumor antigens are unique to a given patient, identification of tumor-specific CD8+ T cells is not routinely feasible. Here, we characterized polyomavirus-specific CD8+ T cells from blood of 17 patients with virus-driven Merkel cell carcinoma (MCC). We identified a 98-gene signature, SPoTT (Signature of Peripheral Tumor-specific CD8+ T cells), that discriminated circulating tumor-specific CD8+ T cells from other T cells in immunotherapy-naïve patients. We observed profound transcriptomic differences among tumor-specific CD8+ T cells from blood versus from tumor. In validation cohorts of MCC, as well as neoantigen-driven cancers, SPoTT was able to identify viral oncoprotein- and neoantigen-specific CD8+ T cells with both sensitivity and specificity above 75%. We also tested a previously described 151-gene signature (NeoTCR_PBL) trained on neoantigen-specific CD8+ T cells and found it was able to recognize MCPyV-specific T cells with sensitivity of 66% and a specificity of 88%. These findings show that circulating tumor-specific CD8+ T cells share fundamental characteristics across diverse tumor antigen types. More broadly, insights into antitumor T cells gained from virus-driven cancers are also likely to be relevant in mutationally-driven cancers.

Aberrant expression of the oncogene SALL4 is associated with stemness, more aggressive cancer phenotype, and reduced patient survival in various tumor types making SALL4 a potential target for cancer immunotherapy. We conducted a transcriptional analysis of SALL4 expression in colorectal cancer (CRC) tissues and demonstrated that SALL4 was overexpressed in primary tumor and paired liver metastasis. Then, we identified the SALL4-derived S9V peptide as a naturally processed peptide that induced specific CD8+ T-cell responses from the peripheral blood of gastrointestinal cancer patients whereas no responses were observed for the peripheral blood of healthy donors. Thereafter, we isolated a SALL4-specific T-cell receptor (TCR) that recognized this peptide in the most common HLA molecule in the Caucasian population, HLA-A2, and used this to develop TCR-engineered T cells. In vitro analysis showed that SALL4 TCR-redirected primary CD8+ T cells exhibited cytotoxic effects against SALL4-expressing tumor cells and produced effector cytokines. In vivo, SALL4-TCR T cells significantly reduced tumor growth and improved survival of tumor-bearing mice. Moreover, SALL4-TCR T cells displayed no toxicity against hematopoietic stem cells. Thus, we conclude that T cells engineered to express a SALL4-specific TCR have the potential to be effective as immunotherapy for solid cancers and pave the way for further clinical development.

Immune checkpoint blockade (ICB) has transformed colorectal cancers (CRCs) therapy, yet the majority of microsatellite-stable (MSS) CRCs remain refractory due to insufficient tumor-immune cell crosstalk. Identifying molecular regulators that modulate the tumor immune microenvironment (TIME) is crucial for expanding ICB efficacy. Here, we identified HNRNPA2B1, an RNA-binding protein prominently upregulated in CRC, as a key driver of immune evasion. Despite low cytotoxicity to normal cells, HNRNPA2B1 rewired the TIME by suppressing Cxcl9/Cxcl10-Cxcr3 signaling, CD8+ T-cell infiltration, and MHC class I antigen presentation, resulting in a non-inflamed ("cold") tumor state. HNRNPA2B1 deletion reprogramed the TIME, enhanced CD8+ T cell-mediated tumor clearance, and sensitized MSS CRCs to ICB. A computational A2B1 score was developed to quantify HNRNPA2B1'simpact on tumor-immune interactions, and showed that it strongly correlated with immune infiltration, epithelial-mesenchymal transition status, and patient prognosis, supporting its potential role as a biomarker for ICB responsiveness in CRC.