Cancer immunology research最新文献

Immunotherapy has emerged as a promising treatment for head and neck squamous cell carcinoma, yet clinical responses remain limited. Elevated expression of interferon-stimulated gene 15 (ISG15), commonly observed in oral squamous cell carcinoma (OSCC), may contribute to this limited efficacy. Although chronic interferon signaling is known to impair CD8+ T-cell function, the specific role of secreted ISG15 in T-cell exhaustion remains unclear. In this study, we report that the analysis of human OSCC datasets revealed significant enrichment of the ISG core score, including ISG15, in tumors compared with adjacent nontumor tissues. Using an in vitro model of human T-cell dysfunction, we found that acute ISG15 exposure enhanced CD8+ T-cell effector functions, whereas prolonged exposure induced severe dysfunction via a CD11a/LFA-1-independent, endocytosis-dependent mechanism. In an immunocompetent orthotopic OSCC model, ISG15-expressing tumors exhibited accelerated growth and recruited more tumor-reactive CD8+ T cells; however, these cells were functionally impaired. Moreover, PD-1 blockade treatment significantly slowed tumor progression and restored T-cell function in ISG15-expressing tumors. Together, our findings reveal that chronic ISG15 exposure promotes CD8+ T-cell dysfunction, but these cells remain responsive to PD-1 blockade. Furthermore, this study identifies ISG15 as a potential biomarker for identifying patients who are likely to benefit from PD-1 blockade therapy.

Early synchronous colorectal liver metastasis (CRLM) represents a clinical condition characterized by the simultaneous presence of primary colorectal cancer and metastatic liver lesions. In this study, we characterized the tissue-specific transcriptomes, phenotypes, and functional relevance of tumor-associated macrophages (TAM) within the tumor microenvironment (TME) of colorectal cancer and CRLM specimens from patients who underwent simultaneous surgical removal of these malignancies. The high-throughput single-cell transcriptional analysis revealed an inverse ratio of inflammatory and immunoregulatory TAMs in the colorectal cancer and CRLM TMEs, along with heterogeneity in both tumoral tissues. Furthermore, we found that inflammatory TAMs in colorectal cancer expressed inhibitory ligands that might support immune escape, thus favoring liver metastatic progression. In contrast, CRLM lesions possessed a highly immunosuppressive milieu characterized by large proliferative CTLA4+ immunoregulatory TAMs and the presence of IL7R+ cytotoxic TAMs. Higher frequencies of these specific TAM subsets in CRLM were associated with shorter disease-free survival and worse patient prognosis. The identification and characterization of immunoregulatory TAMs preferentially enriched in CRLM is key for the development of novel immunotherapeutic strategies aimed at boosting anticancer immune responses within the TME.

Combination chemotherapy and immunotherapy are effective against advanced gastric cancer. However, T-cell exhaustion in the tumor microenvironment may decrease the immune response and compromise the effectiveness of immunotherapy. Herein, we report the potential role of EBI3 in promoting T-cell exhaustion and its mechanism in gastric cancer, showing high expression of EBI3 in gastric cancer. Correlation analysis between EBI3 expression level and clinical-pathologic features indicated significant associations with tumor stage, nodal staging, pathologic stage, and degree of tumor differentiation. EBI3 expression levels correlated with a state of high CD8+ T-cell exhaustion, as identified by transcriptome sequencing and mouse orthotopic gastric cancer models. On exposure to EBI3, CD8+ T cells showed signs of cell exhaustion as reduced cytokine secretion and increased expression of inhibitory receptors in in vitro/vivo studies. Mechanistically, EBI3 induced T-cell exhaustion by promoting the phosphorylation of STAT4 and upregulating the transcription of downstream target genes CCL5 and IL10. An anti-EBI3 heptapeptide (Val-Tyr-Leu-His-Trp-His-Asp) was developed, which competitively bound EBI3 and reversed the induction of T-cell exhaustion. Taken together, we identified a T-cell exhaustion mechanism in gastric cancer via the EBI3-STAT4-IL10/CCL5 axis and developed an anti-EBI3 heptapeptide with an antagonistic function. These findings provide a potential immunotherapeutic target and support the development of EBI3-based interventions to enhance immunotherapy efficacy in gastric cancer.

Myeloid cells-including monocytes, macrophages, dendritic cells, and granulocytes-are critical architects of the tumor microenvironment, in which they exert diverse functions ranging from immunosuppressive to immunostimulatory. Advances in single-cell omics and high-dimensional immune profiling have unveiled the remarkable heterogeneity and plasticity of these cells, revealing lineage-specialized functions that shape cancer immunity. These discoveries have sparked growing interest in therapeutically targeting myeloid cells as a next-generation strategy in cancer immunotherapy. As a complementary or alternative approach to T cell-centered immunotherapies, myeloid-directed therapies offer unique opportunities to reprogram the immune landscape, enhance antitumor responses, and overcome resistance mechanisms. In this review, we highlight recent discoveries in myeloid cell biology in cancer and discuss emerging therapeutic targets, with an emphasis on antibody-based therapies that have reached clinical development. We further provide perspective on translational challenges to implement these approaches into the clinic and discuss how Fc-engineering and rational antibody design can optimize myeloid cell engagement and amplify their immune effector functions. Together, these advances position myeloid-directed immunotherapies as a promising approach to enhance the efficacy and durability of cancer treatment.

Treating radioresistant tumors like glioblastoma multiforme remains a challenge exacerbated by their immunosuppressive nature. Radiotherapy (RT) plays an immunomodulatory role, exerting both immunosuppressive and immunostimulatory effects. The nature of these effects depends on the total dose, dose per fraction, dose delivery method, and treatment length. Hypofractionation is observed to tip the balance toward immune stimulation. However, the use of hypofractionation is restricted in bulky tumors, such as gliomas, because of the high risk of toxicity. Therefore, finding new strategies leading to more favorable immune responses while reducing normal tissue toxicities could improve cancer treatment. In this study, we examine antitumoral immune responses to proton minibeam RT (pMBRT). Its immunomodulatory effects are not fully understood. To explore this, we conducted an in-depth characterization of the immune response to a curative dose of pMBRT in a preclinical orthotopic rat model of glioblastoma. Our findings revealed a close association between pMBRT and the immune response. pMBRT increased lymphocyte density in tumors more effectively than conventional proton therapy. Single-cell transcriptomics identified several immune cell types and unique transcriptional changes in tumor immune cells following pMBRT, including increased antibody production, chemotactic cytokine expression, and IFN responses. These results underscore the critical role of adaptive immunity, specifically T cells, in pMBRT's mechanism. The potential of pMBRT to trigger an antitumor immune response in a single RT session with minimal damage to healthy tissue makes it a promising candidate for future clinical trials and radioimmunotherapy combinations.

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.

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.

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.