Cancer immunology research最新文献

Chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable efficacy against hematologic malignancies but has struggled to achieve comparable success in solid tumors. A key obstacle in solid tumors is the extracellular matrix (ECM), which impedes CAR T-cell infiltration. In clinical trials, neuroblastoma has shown responsiveness to GD2-directed CAR T-cell therapy; however, the failure of GD2.CAR T cells to effectively clear bulky disease-characterized by dense ECM-highlights the critical challenge of infiltration. In this study, we demonstrate that GD2.CAR T cells exhibit a unique infiltration restriction compared with other CAR T cells and endogenous T cells. A separate analysis of clinical datasets identified MMP7 and SPP1 [which encodes osteopontin (OPN)] as candidate genes to improve the infiltration of GD2.CAR T cells as these were upregulated in tumor-infiltrating leukocytes. MMP-7 and OPN overexpression enhanced CAR T-cell extravasation and interstitial movement in ECM-dense environments in vitro. Overexpression of either OPN or MMP-7 significantly improved tumor infiltration in a xenograft model of neuroblastoma. This resulted in improved tumor control and a survival extension in OPN-GD2.CAR T cell-treated mice compared with unmodified GD2.CAR T cells. OPN overexpression did not increase off-target infiltration into healthy tissues or promote tumor metastasis, highlighting its potential for safe therapeutic application. Our study provides a framework for further exploration of gene modifications to improve CAR T-cell infiltration in solid tumors and identifies OPN as a candidate to explore in this regard. See related Spotlight by Gasparetto and Chiarle, p. 1698.

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.

Pancreatic adenocarcinoma (PDAC) has a dismal survival rate due to limited effective therapies. Although studies have focused on the influence of innate immune cells on adaptive immune cell functions, few have explored interactions between innate immune cells, which modulate the PDAC tumor microenvironment (TME). Macrophages are responsible for the clearance of neutrophil-mediated inflammation in physiologic, resolving immune responses; however, both of these cell types coexist in the TME, suggesting a failure of macrophages to clear neutrophils in PDAC. We sought to determine how neutrophil extracellular traps (NET), neutrophil release of decondensed chromatin, and intracellular contents affect monocyte/macrophage populations in the PDAC TME. Utilizing samples from patients with PDAC, we demonstrated elevated levels of the monocyte chemokine CCL2 in plasma, as well as elevated NET citrullinated histone H3 and the pan-macrophage marker CD68 in the PDAC TME via fluorescent IHC. To determine how NETs affected macrophage populations in the PDAC TME, we targeted NETs with DNase I treatment to digest extracellular DNA released from NETs or with genetic knockout of PAD4, an enzyme required for NET formation. NET depletion resulted in an elevation in the pan-macrophage marker F4/80. The depletion led to an increased T-cell stimulatory signal, CD80, whereas the protumor macrophage marker CD206 was decreased. We further demonstrated that macrophages in the NET-deficient PDAC TME may be recruited through the CCL2/CCR2 axis, and CCL2 was released from tumor cells and macrophages in the presence of IFNγ. Taken together, our findings reveal that inhibition of NETs can prime the innate immune response toward an antitumor phenotype.

Recent studies have explored the composition of the tumor microenvironment (TME) in diffuse large B-cell lymphoma (DLBCL) However, cell-to-cell interactions, along with the spatial organization of DLBCL TME and their impact on patient outcomes, have remained poorly characterized. We applied multiplex immunofluorescence, cell phenotyping, and neighborhood analysis to investigate 1,218,756 single cells in 99 samples from patients with primary DLBCL. We identified 17 cell phenotypes and 10 recurrent cellular neighborhoods (RCN) across samples, subdividing DLBCLs into immune-poor areas and areas with diverse immune cell infiltrates. Avoidance of B cells and PD-1+ T cells was associated with less aggressive clinical characteristics and favorable survival. Likewise, the proximity of CD8+ T cell-rich and immune-poor RCNs translated to favorable patient outcomes, and the proximity of PD-L1+ B cell-rich and CD8+ T cell-rich RCNs to unfavorable patient outcomes. Our findings provide insights into the spatial interactions and organization of DLBCL TME with implications for patient outcomes.

The effectiveness of T cell-based immunotherapy depends on durable T-cell responses that can efficiently eliminate tumor cells. NKG7 was discovered three decades ago as a protein associated with lytic granules. However, only studies published over the past 5 years have contributed substantially to our understanding of NKG7 in T-cell biology. NKG7 has been recognized as an important T-cell functional marker in responses to immune checkpoint inhibitor therapy and in the prognosis of certain cancers. Besides its role in the generation, trafficking, and release of lytic granules, which is critical for efficient T-cell cytotoxicity against tumor cells, NKG7 has been identified as a key negative regulator of mTORC1 activity. By restraining mTORC1 activity, NKG7 promotes T-cell longevity and memory generation after infection. Importantly, NKG7 upregulation has demonstrated therapeutic potential in preclinical T-cell therapy for cancer. Collectively, NKG7 is emerging as a promising biomarker and therapeutic addition to T cell-based immunotherapies.

Tumor-associated macrophages (TAM) and regulatory T cells (Treg) are major immune components of the tumor microenvironment, promoting tumor growth and limiting the efficacy of chemotherapy in almost all cancer indications. Although Tregs are well known for their immunosuppressive activity toward the adaptive immune system, less is known about their regulatory activity toward the innate compartment. In this study, we have shown that in human and mouse lung cancer, chemotherapy transiently reduced Treg number and switched the mononuclear phagocyte (MP) landscape toward not only a proinflammatory signature but also an increased TGFβ-expressing TAM accumulation over time. Preventing Treg recovery further increased the recruitment of monocytes and limited TGFβ expression upon TAM differentiation, demonstrating that Tregs dampen the proinflammatory status of the MP compartment induced by chemotherapy and promote tumor relapse. Anti-TNFR2 antibody treatment during the Treg recovery phase affected the direct interaction between Tregs and MPs, increased the proinflammatory signature of the MPs, and improved survival in the mouse model. Targeting the cross-talk between tumor-associated Tregs and the MP compartment limits the reconstitution of an anti-inflammatory environment following chemotherapy and improves therapeutic outcome.