Cancer immunology research最新文献

Advanced sarcomas have limited treatment options after standard therapy, and therefore we investigated the efficacy and safety of sintilimab plus anlotinib in this setting. Patients age 18 to 75 years with advanced sarcomas and prior systemic therapy were enrolled. Patients with untreated, primary chemotherapy-resistant tumor types, such as alveolar soft-part sarcoma and clear-cell sarcoma, were also included. Patients received sintilimab 200 mg (day 1) and anlotinib (8, 10, or 12 mg investigator-chosen, day 1-14) every 3 weeks. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse events (AE). The predictive value of tertiary lymphoid structure (TLS) was explored. A total of 42 patients were enrolled, and 40 (95.2%) patients were non-alveolar soft-part sarcoma. The ORR and DCR were 30.9% [95% confidence interval (CI), 16.4%-45.5%] and 76.2% (95% CI, 62.8%-89.6%), respectively, with a median follow-up duration of 15.4 months, and the median PFS was 5.0 months (95% CI, 2.8-10.2). The median OS was not reached. The most common AEs included elevated lactate dehydrogenase (28.57%), hypoproteinemia (21.43%), and increased thyroid-stimulating hormone (21.43%). The most common ≥ grade 3 AEs were hypertension (4.76%) and hyponatremia (4.76%). Two serious AEs (one hepatitis and one intestinal perforation) were recorded. The ORR in TLS-positive patients (n = 7) was significantly higher than that in TLS-negative patients (n = 28; 71.4% vs. 25.0%, P = 0.033). Therefore, sintilimab plus anlotinib demonstrated promising antitumor activity with manageable toxicity in advanced sarcomas, particularly among TLS-positive patients.

Antibody-based therapies have revolutionized cancer treatment but have several limitations. These include downregulation of the target antigen, mutation of the target epitope, and, in the case of antibody-drug conjugates (ADC), resistance to the chemotherapy warhead. As TROP2-targeted therapy with ADCs yields responses in TROP2+ solid tumors, but the responses lack the durability observed with other immunotherapy-based approaches, we developed TROP2-targeting chimeric antigen receptor (CAR) T cells as an alternative. The TROP2-directed CAR T cells showed high potency against multiple solid tumor models. Moreover, TROP2-directed CAR T-cell therapy preserved high potency in models of ADC resistance and could be further engineered to prevent cell therapy resistance. This was achieved by leveraging fully human single-domain (VH-only) binder discovery to rationally engineer dual epitope binding-based (biparatopic) CARs. This work highlights the potency of CAR T-cell therapies and how rational engineering leveraging dual-VH targeting domains can overcome resistance pathways to current therapies. In future work, the CAR engineering approaches presented here can serve as a platform to be partnered with other strategies to address the suppressive tumor microenvironment.

Ovarian cancer remains a major health threat with limited treatment options available. It is characterized by an immunosuppressive tumor microenvironment (TME) maintained by tumor-associated macrophages (TAM), hindering antitumor responses and immunotherapy efficacy. In this study, we showed that targeting retinoblastoma protein (Rb) by disruption of its LxCxE cleft pocket caused preferential cell death in Rbhigh M2-polarized or M2-like Rbhigh immunosuppressive TAMs by induction of endoplasmic reticulum stress, p53, and mitochondria-related cell death pathways. A reduction of protumor immunosuppressive macrophages from TME in vivo resulted in enhanced T-cell infiltration and T-cell antitumor response and inhibited cancer progression. We demonstrated increased Rb expression in TAMs in women with ovarian cancer, which was associated with poorer prognosis. Ex vivo, we showed analogous cell death induction by therapeutic Rb targeting in TAMs in post-surgery ascites from patients with ovarian cancer. Overall, our data identify the therapeutic targeting of the Rb LxCxE cleft pocket as a promising approach for ovarian cancer treatment through depletion of immunosuppressive Rbhigh TAMs and re-shaping of the TME immune landscape.

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.

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.