Cancer immunology research最新文献

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.

T-cell therapies have transformed cancer treatment. Although surface glycans have been shown to play critical roles in regulating T-cell development and function, whether and how the glycome influences T cell-mediated tumor immunity remains an area of active investigation. In this study, we show that the intratumoral T-cell glycome is altered early in human colorectal cancer, with substantial changes in branched N-glycans. We demonstrated that CD8+ T cells expressing β1,6-GlcNAc-branched N-glycans adopted an exhausted phenotype, marked by increased PD1 and Tim3 expression. CRISPR-Cas9 deletion of key branching glycosyltransferase genes revealed that Mgat5 played a prominent role in T-cell exhaustion. In culture-based assays and tumor studies, Mgat5 deletion in CD8+ T cells resulted in improved cancer cell killing. These findings prompted the assessment of whether MGAT5 deletion in anti-CD19 chimeric antigen receptor (CAR) T cells could enable this therapeutic modality in a solid tumor setting. We showed that MGAT5 knockout anti-CD19-CAR T cells inhibited the growth of CD19-transduced tumors. Together, these findings show that MGAT5-mediated branched N-glycans regulate CD8+ T-cell function in cancer and provide a strategy to enhance the antitumor activity of native and CAR T cells.

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.