Cancer immunology research最新文献

There are limited therapeutic options for patients with advanced sarcomas, which leads to dismal outcomes for children and adults. Although chimeric antigen receptor (CAR) T cells hold promise for treating advanced sarcomas, this approach is constrained by a paucity of effective targets. Our previous clinical study identified endoglin (ENG/CD105), a TGFβ coreceptor, as a target of the endogenous immune response in a patient with sarcoma who exhibited an exceptional response to HER2-targeted CAR T-cell therapy. ENG is expressed on various sarcomas, cancer-associated fibroblasts, and neoangiogenic vessels and therefore offers comprehensive tumor targeting. Furthermore, ENG knockout in sarcoma cells reduces their invasiveness, highlighting its potential as a therapeutic target. Accordingly, we designed a second-generation human ENG-targeting CAR molecule signaling through the CD28 endodomain and retrovirally transduced primary human T cells with this CAR. ENG CAR T cells exhibited strong antigen-specific cytokine release, robust proliferation, memory formation, and cytotoxic function against various sarcoma cell lines. Their cytotoxicity remained unaffected by the presence of soluble ENG or its natural ligand, bone morphogenetic protein-9. Furthermore, ENG CAR T cells disrupted multicellular tumor spheroids in vitro, overcoming tumor compactness and the stromal barrier created by cancer-associated fibroblasts, which are critical challenges in sarcoma CAR T-cell therapy. In orthotopic xenograft models of sarcomas, ENG CAR T-cell treatment resulted in control of tumor growth and metastasis, leading to survival extension. In summary, our study describes the involvement of ENG in sarcoma metastasis and validates our human ENG CAR T cells as a potential therapeutic for advanced sarcomas.

Despite the effectiveness of anti-PD-1/PD-L1 mAbs against various cancers, resistance remains a significant issue among patients. The immunosuppressive T-cell immunoreceptor with Ig and ITIM domains/CD155 axis has emerged as a key mechanism contributing to this resistance. However, the intricacies of CD155 expression are not fully elucidated. In this study, we aimed to identify the key molecules involved in the regulation of CD155 expression and explore their role in modulating CD155 within the tumor microenvironment (TME). By using clustered regularly interspaced palindromic repeats (CRISPR) screening, we identified dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A (DYRK1A) as one of the key regulators of CD155 expression. Subsequent inhibition of Dyrk1a through CRISPR/CRISPR-associated protein 9 technology or treatment with DYRK1A inhibitors mitigated PD-1 blockade resistance. Moreover, in certain head and neck squamous cell carcinoma cell lines, cetuximab-mediated EGF receptor blockade reduced CD155 expression by targeting downstream PI3K/Akt signaling. In patients with head and neck squamous cell carcinoma (n = 96), CD155 expression correlated with Akt phosphorylation, particularly affecting PD-1 blockade resistance in those with high CD8+ T-cell infiltration. These findings underscore the role of the PI3K/Akt signaling pathway in regulating CD155 expression, which may influence resistance to PD-1 blockade therapies in a variety of cancers, particularly those characterized by an inflamed TME. This study suggests that targeting the PI3K/Akt pathway could overcome resistance, particularly in cancers with an inflamed TME and high CD155 expression.

Antigen presentation by dendritic cells (DC) is crucial in activating T cells. DCs capture, process, and present antigens to T cells, making them attractive vaccine vehicles. However, most DC cancer vaccines have had limited clinical efficacy, suggesting a need to increase their potency. We report that high levels of omega-3 fatty acids in mice significantly prolonged lifespan and reduced tumor growth and body weight loss. This effect was mediated in part by more effective DC antigen presentation. DCs derived from Tg(CAG-fat-1)Jxk/J transgenic mice expressing high omega-3 lipid levels were better vaccine vehicles than wild-type (WT) DCs in treating cancers in WT mice and in stimulating CD8+ T-cell responses in vitro and in vivo. Although no effect on the levels of expression of costimulatory molecules was detected, we discovered a marked enhancement of T-cell dwell time on DCs. We also observed that differentiating DCs from WT bone marrow in the presence of omega-3 lipids increased DC antigen presentation capacity in vitro, suggesting a potential approach to enhance DC-based cancer vaccine efficacy.

Macrophages expressing Trem2 play a pivotal role in promoting nonalcoholic steatohepatitis (NASH; also known as metabolic dysfunction-associated steatohepatitis) progression to hepatocellular carcinoma (HCC). Despite the widespread clinical use of anti-PD-1 immune checkpoint blockade, its therapeutic efficacy in NASH-driven HCC remains suboptimal. This study investigates the mechanisms by which NAM Trem2 influences the response of NASH-driven HCC to immunotherapy. Clinical analysis revealed that elevated Trem2 expression in NASH is positively correlated with the accumulation of neutrophil extracellular traps (NET) and infiltration of PD-1+Eomes+CD8+ T cells and regulatory T cells. Myeloid-specific knockout of Trem2 (Trem2Δmye) led to impaired macrophage reprogramming, resulting in the accumulation of proinflammatory Ly6ChiCX3CR1lo macrophages, which enhanced degradation of NETs in NASH. Trem2Δmye also disrupted TGFβ production via P-Syk-dependent efferocytosis, collectively suppressing the differentiation of PD-1+Eomes+CD8+ T cells and regulatory T cells. The efficacy of anti-PD-1 therapy in inhibiting NASH-driven HCC progression was also significantly enhanced by Trem2Δmye, primarily through the downregulation of Treg CXCR4 expression mediated by increased NET degradation. These therapeutic effects were further amplified when combined with the CXCR2 inhibitor AZD5069. Our findings identify Trem2 as a central regulator of the NASH-driven HCC immunosuppressive niche and suggest a combinatorial therapeutic strategy that targets both myeloid reprogramming and NETosis to overcome immunotherapy resistance in metabolic liver cancer progression.

Therapies using NK cells that express chimeric antigen receptors (CAR-NK) have been successfully employed against hematologic malignancies. However, solid tumors resist CAR-NKs partly by enriching tumor microenvironments with ligands for NK cell inhibitory receptors. Although the NK inhibitory receptor T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) has been implicated in impaired antitumor activity of endogenous NK cells, the consequences of TIGIT expression on engineered CAR-NKs have not been explored. To address this gap, we compared TIGIT-expressing and TIGIT-deleted human CAR-NKs targeting the GD2 solid tumor antigen in tumor immune microenvironment co-cultures and in vivo tumor immune microenvironment xenografts designed to mimic the immunosuppressive environment of solid tumors. TIGIT-deleted GD2.CAR-NKs exhibited antitumor activity, expanded, and persisted within TIGIT ligand-enriched solid tumor environments, whereas TIGIT-expressing CAR-NKs did not. Mechanistic experiments revealed that the improved tumor control resulting from TIGIT loss on CAR-NKs was not dependent on DNAM-1 activation or enhanced cytotoxic potential but rather on downregulation of cell adhesion molecules, weakened cell avidity, and reduced synapse contact duration that, in concert, improved serial killing and allowed more efficient tumor destruction. Our study highlights a noncanonical role for TIGIT in modulating CAR-NK activity that may guide strategies to overcome inhibitory NK receptors like TIGIT and improve the efficacy of CAR-NKs against solid tumors.

Tumor-associated macrophages (TAM) are key regulators of tumor immunity. With advances in single-cell analyses, secreted phosphoprotein 1 (SPP1)-positive TAMs have been observed across multiple tumor sites. However, their clinical relevance and phenotypic characteristics in clear-cell renal cell carcinoma (ccRCC) have not been comprehensively delineated. Using patient-level data from two in-house cohorts (n = 355), we explored the relationship between SPP1+ TAM infiltration and therapeutic response and prognosis in ccRCC. Four publicly available datasets consisting of 1,741 patients with ccRCC were included for external validation. Cytometry by time-of-flight and flow cytometry were utilized to phenotype SPP1+ TAMs and establish their impact on CD8+ T cells. Furthermore, we established an ex vivo culture system to test the potential therapeutic value of targeting SPP1 alone and in conjunction with PD-1 inhibitors in ccRCC. We found that patients with high SPP1+ TAM infiltration exhibited worse response to immunotherapy and dismal prognosis in ccRCC. SPP1+ TAMs exhibited an immunosuppressive and protumor phenotype, and were related to impaired effector function and terminal differentiation of CD8+ T cells. Blockade of SPP1 mitigated the protumor tumor microenvironment and reinvigorated CD8+ T-cell function. Combining PD-1 blockade with SPP1 blockade boosted the expansion of CD8+ T cells and enhanced antitumor efficacy. Together, these data indicate that elevated infiltration of SPP1+ TAMs is related to worse response to immunotherapy and dysfunction of CD8+ T cells in ccRCC. We conclude that SPP1 may serve as a potential therapeutic target in ccRCC.

Vγ9Vδ2 (TCRVγ9+ TCRVδ2+) T cells are promising immunotherapeutic targets with effective antitumor properties in both in vitro and preclinical models of triple-negative breast cancer (TNBC). However, no information about their potential role in the context of human TNBC progression and response to immunotherapy has been reported. One key reason for this is the scarcity of Vγ9Vδ2 T-cell infiltrates relative to their Vδ1 (TCRVδ1+) and αβCD8 (TCRαβ+ CD8αβ+) T-cell counterparts. We provide comprehensive single-cell profiling of Vγ9Vδ2 T cells from patients with TNBC, prior to and following PD-(L)1 blockade therapy. We report that baseline Vγ9Vδ2 T-cell infiltrate expressing a unique cytotoxic type I phenotype could be associated with improved survival in patients with TNBC. Vγ9Vδ2 T cells harboring characteristics of enhanced antitumor activity (KLRC1+) were further associated with improved response to PD-(L)1 blockade therapy in patients with TNBC. Vγ9Vδ2 T cells had low expression levels of T-cell exhaustion (PD-1LowTOXLow) and T-cell receptor signaling hallmarks compared with Vδ1 and αβCD8 T cells, along with skewed differentiation profiles toward early effector memory phenotypes, both before and after anti-PD-1 therapy in TNBC tumors. Consistently, we observed limited activity of anti-PD-1 on tumor-infiltrating Vγ9Vδ2 T cells. In vitro, the use of anti-butyrophilin-3A antibodies in addition to anti-PD-1 reinvigorated the cytotoxic type I functions of peripheral Vγ9Vδ2 T cells from patients with breast cancer. Together, these data provide a rationale for Vγ9Vδ2 T cell-based combination therapy in patients with TNBC.

Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy has revolutionized the prognosis of patients with relapsed/refractory multiple myeloma. Regrettably, despite unprecedented overall response rates achieved with this approach, most patients eventually relapse. One of the primary reasons for this is the complete loss or reduced expression of BCMA on the malignant plasma cell surface. Consequently, new therapeutic targets are under investigation. Another potential therapeutic approach involves the use of CAR T cells targeting two tumor antigens. In this study, we developed and validated a monospecific CAR targeting CD229, which was effective in in vitro and in vivo NOD.Cg-Prkdcscid Il2rdtm1Wjl/SzJ mouse models with both homogeneous and heterogeneous BCMA expression. Additionally, we created a bicistronic CAR T cell targeting both CD229 and BCMA, which demonstrated efficacy in models with homogeneous BCMA expression, in heterogeneous models featuring small clonal populations with biallelic BCMA deletion, and in cases with reduced BCMA expression both in vivo and in vitro. Regarding "on-target off-tumor toxicity," no fratricide was observed among CAR T cells, but there was a limited elimination of nonactivated T cells. The immune pressure exerted by anti-CD229 CAR T cells led to the loss of the CD229 antigen expression in some instances. In summary, this work underscores the potential utility of CD229 alone or in combination with BCMA as an immunotherapeutic target in multiple myeloma, especially in cases marked by diminished or absent BCMA expression.

Tumor-associated macrophages (TAM) are a universal feature of cancers but variably influence outcomes and treatment responses. In this study, we used a photoconvertible mouse to distinguish newly entering, monocyte-derived TAMs (mdTAM) that were enriched at the tumor core from resident-like TAMs that localized with fibroblasts at the tumor-normal interface. The mdTAM pool was highly dynamic and continually replenished by circulating monocytes. Upon tumor entry, these monocytes differentiated down two divergent fate trajectories distinguished by the expression of MHC class II. MHC-II+ mdTAMs were functionally distinct from MHC-II- mdTAMs, demonstrating increased capacity for endocytosis and Fc-gamma receptor-mediated phagocytosis, as well as proinflammatory cytokine production. Both mdTAM subsets showed reduced expression of inflammatory transcripts and increased expression of PD-L1 with increasing tumor dwell time. Treatment with anti-PD-L1 skewed mdTAM differentiation toward the MHC-II+ fate and attenuated the anti-inflammatory effects of the tumor environment. Anti-PD-L1 enhanced mdTAM-CD4+ T cell interactions, establishing an IFNγ-CXCL9/10-dependent positive feedback loop. Altogether, these data resolve distinct temporal, spatial, and functional properties of TAMs and provide evidence of subset-specific effects of PD-L1 blockade.

Diacylglycerol kinase α (DGKα) and DGKζ are lipid kinases that negatively regulate T-cell signaling through diacylglycerol metabolism, making them attractive targets for next-generation immunotherapy. In this study, we report the discovery and preclinical characterization of the clinical-stage DGKα and DGKζ lipid kinase inhibitor, BMS-986408. BMS-986408 binds to the accessory subdomain of the catalytic domain and inhibits DGKα/ζ through a mechanism of action that includes competitive inhibition for the diacylglycerol substrate, subcellular translocation to the plasma membrane, and proteosome-dependent degradation. DGKα/ζ inhibition markedly improved the therapeutic benefit of PD-1 therapy by unleashing T-cell responses in the tumor while also amplifying the priming and expansion of tumor-reactive T cells in tumor-draining lymph nodes. Simultaneous inhibition of both DGKα and DGKζ was required to maximize combination benefit with PD-1 therapy. Furthermore, we observed in non-small cell lung cancer (NSCLC) patient samples that DGKα and DGKζ were broadly expressed in tumor-infiltrated T cells and that combination therapy invigorated a robust cytokine response in organotypic tumors derived from patients with NSCLC, supporting the clinical evaluation of this combination in patients with NSCLC. BMS-986408 also markedly improved CD19-targeted CAR T-cell therapy efficacy by overcoming hypofunctionality, insufficient expansion, and lack of costimulatory ligands. BMS-986408 represents a critical step toward evaluating the broad immunotherapy potential of DGKα/ζ inhibitors in patients with cancer.