Cancer Immunology, Immunotherapy最新文献

Objectives: In recent years, immune checkpoint inhibitors have shown promise as neoadjuvant therapies in the treatment of locally advanced oral squamous cell carcinoma (OSCC). However, the factors affecting the tumor response to immune checkpoint inhibitors (ICIs) remain unclear. This study aimed to analyze the impact of neoadjuvant chemoimmunotherapy (NACI) on the tumor microenvironment of OSCC via single-cell RNA sequencing, with the goal of optimizing treatment strategies.

Methods: We analyzed biopsy, primary tumor, matched metastatic lymph node, and normal lymph node samples from four patients with OSCC receiving two cycles of tislelizumab (200 mg), albumin-bound paclitaxel (260 mg/m²), and cisplatin (60-75 mg/m²), with 3-week intervals between each cycle. This study explored the tumor microenvironment characteristics of tumors and metastatic lymph nodes in response to NACI.

Results: We identified two major tumor cell subpopulations (C9 and C11), and patients with high expression of C11 subgroup-specific genes had a lower survival rate. FOXP3+ CD4 eTreg cells were found to potentially suppress the immune response. We found that NACI enhances antitumor immunity by promoting the proliferation of granzyme-expressing CD8+ T effector cells while simultaneously diminishing the effect of CD4+ T cells on Treg-mediated immune suppression. Furthermore, NACI was effective in suppressing inflammatory processes mediated by myeloid cells in tumors, contributing to its antitumor effects. The CCL19+ fibroblastic reticular cell (FRC) subgroup was significantly associated with the efficacy of NACI in patients with OSCC. We found that CCL19+ FRCs primarily exert their antitumor effects through interactions with CD8+ T lymphocytes via the -CXCL12‒CXCR4 axis.

Conclusion: We explored the immune landscape of primary OSCC tumors and metastatic lymph nodes in relation to clinical response to NACI. Our findings offer valuable insights into patient treatment responses and highlight potential new therapeutic targets for the future management of OSCC.

The histone deacetylase inhibitor MS275 (Entinostat) demonstrates anti-tumor effects against various types of solid tumors in vitro. But its effectiveness in clinical trials is limited. The underlying reasons remain to be determined. The purpose of this study was to explore how to enhance the anti-tumor effects of MS275 in colorectal cancer (CRC). Our data showed that MS275 inhibited CRC cell proliferation and induced apoptosis, irrespective of gene mutation status. However, MS275 did not effectively suppress tumor growth in the AOM-DSS CRC model as observed in vitro. MS275 decreased CD3+T cell tumor infiltration and created an immunosuppressive microenvironment in the AOM-DSS CRC model. MS275 also decreased the percentage of CD8+T cells while increasing the percentage of CD4+T cells in mesenteric lymph nodes. Reshaping tumor immune response may contribute to the less pronounced anti-tumor effect of MS275 observed in vivo compared to in vitro. Further study showed that the increased PD-L1 expression in CRC both in vivo and in vitro following MS275 treatment. Moreover, the anti-tumor effects of MS275 were enhanced by combining it with an anti-PD-1 antibody. This combination treatment also increased CD8+T cell tumor infiltration in the AOM-DSS CRC model, thereby leading to an anti-tumor immune response. Therefore, the combination of MS275 and anti-PD-1 immunotherapy represents a potential strategy for low PD-L1 expression tumors and should be considered a promising treatment approach for colon cancer.

Background: Improving pathological complete response (pCR) rate is currently the main goal of neoadjuvant therapy for locally advanced esophageal squamous cell carcinoma (LA-ESCC). However, improved pCR rates do not consistently translate into better prognosis, likely due to regimen-specific pCR heterogeneity. We investigated this heterogeneity and potential biomarkers between two common neoadjuvant regimens.

Methods: We included 445 LA-ESCC patients from four centers, with 228 receiving neoadjuvant chemoradiotherapy (nCRT) and 217 undergoing neoadjuvant chemotherapy combined with immunotherapy (nICT). Propensity score matching ensured group comparability. We assessed pCR rates and their associations with overall survival (OS), disease-free survival (DFS), and recurrence patterns. Immune-related biomarkers were investigated through RNA sequencing and immune infiltration analysis, then validated via multiplex immunofluorescence staining.

Results: Overall, pCR was associated with significantly higher DFS (HR = 0.3 [0.18-0.5], P < 0.01) and OS (HR = 0.19 [0.08-0.41], P < 0.01) compared to non-pCR. The nICT group had a lower pCR rate than the nCRT group (27.2% vs. 42.9%) but demonstrated comparable prognosis and reduced distant metastasis. Among pCR patients, DFS was significantly better in the nICT group (HR = 0.2 [0.05-0.86], P = 0.031), with a trend toward improved OS. Immune analysis revealed increased CD8 + T cell infiltration, particularly CD69 + CD8 + tissue-resident memory T cells (TRM), in the nICT pCR group. The proportion of CD69 + CD8 + TRM cells was significantly linked to improved DFS (P = 0.016) and OS (P = 0.015), suggesting they may be superior prognostic markers compared to pCR rates.

Conclusions: The pCR obtained from different neoadjuvant treatments has distinct prognostic outcomes. The CD69 + CD8 + TRM, as a potential prognostic predictor, warrants further investigation.

The CLL1-targeted chimeric antigen receptor T (CAR-T) cell therapy offers a novel therapeutic approach for refractory or relapsed acute myeloid leukemia (AML).The targeted elimination of tumor cells by CLL1 CAR-T therapy also induces cytotoxic effects on neutrophils, leading to a severe granulocytopenia, thereby significantly increasing the risk of infectious complications during CAR-T therapy. However, the infectious complications associated with this strategy have not been comprehensively investigated. The objective of this study was to evaluate the incidence rate of infectious complications within a 28-day period in a cohort of 51 patients who underwent CLL1 CAR-T cell infusion. Meanwhile, the univariate and multivariate analyses were employed to access the risk factors of infectious complications during CLL1 CAR-T therapy. The study observed a total of 46 infection events in 32 out of 51 patients (63%), with the median onset of infection occurring at 9 days following CAR-T cell infusion. The cumulative incidence of infection events within 28 days was 56.9% (95%CI: 50.4-61.3%), with bacterial and fungal infections being the most prevalent early infection events. The results of multivariate analysis revealed that a lower neutrophil counts prior to lymphodepletion chemotherapy (OR = 3.875, P = 0.041) and more severe complications of cytokine release syndrome (OR = 4.141, P = 0.037) were identified as independent risk factors associated with an increased likelihood of early infection events. This study examined the distribution of early infection events and identified potential risk factors, with the goal of offering guidance to physicians on implementing more effective intervention strategies to decrease treatment-related mortality rates and improve patient prognosis. This study has been registered in the Chinese Clinical Trial Registry (Trial registration number: ChiCTR2000041054).

The TAM receptor family is getting more and more attention in the field of tumour immunity. Activation of TAM receptors not only aids in the survival and multiplication of tumour cells but also increases their likelihood of invading other cells and spreading. In addition, activation of TAM receptors helps to inhibit the anti-tumour immune response, allowing tumour cells to evade immune surveillance. In terms of therapeutic strategies, a number of inhibitors targeting TAM receptors are in preclinical and clinical development. Despite significant progress in clinical trials in recent years, challenges remain. This review delves into the kinetic characteristics of the TAM receptor family, their dual role in tumour immunity, and the transmission process of downstream signalling pathways. Based on this, we analysed and summarised the unique strategies and combination therapies for regulating tumour immunity using TAM receptor inhibitors. It not only helps to elucidate the key role of TAM receptors in tumour immunity but also provides new perspectives and strategies for future tumour therapy.

Factors associated with outcomes of chimeric antigen receptor (CAR)-T cell therapy in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have not been fully elucidated. We explored the impact of the prelymphodepletion (pre-LD) lymphocyte to monocyte ratio (LMR) and its ratio to lactate dehydrogenase (LDH) (LMR/LDH) on the efficacy and prognosis of 60 patients with R/R DLBCL undergoing CAR-T cell therapy. The optimal cutoff values for pre-LD LMR and LMR/LDH were 3.583 and 0.0103, respectively. The overall response rate (ORR)s were higher in patients with high pre-LD LMR or LMR/LDH than those with low pre-LD LMR or LMR/LDH (ORR, 100% vs. 65.79%, P = 0.006 and 96.15% vs. 38.24%, P < 0.0001, respectively). Pre-LD LMR/LDH was an independent factor associated with ORR (P = 0.010, odds ratio = 18.757; 95% confidence interval [CI] 2.046-171.975) by multivariate logistic regression analysis. Patients with high pre-LD LMR/LDH had significantly longer progression-free survival (PFS) (median PFS, 29.73 vs. 2.47 months, P < 0.0001) and overall survival (OS) (median OS, not reached vs. 7.4 months, P = 0.0002) than those with low pre-LD LMR/LDH. Multivariate Cox regression analysis showed that pre-LD LMR/LDH and ORR were independent factors affecting PFS (P = 0.030, hazard ratio [HR] = 2.561; 95% CI 1.093-5.999 and P = 0.024, HR = 2.202; 95% CI 1.22-4.369, respectively); pre-LD LMR/LDH was an independent factor affecting OS (P = 0.029, HR = 3.331; 95% CI 1.131-9.807). In conclusion, the pre-LD LMR/LDH was an independent factor associated with ORR and an independent prognostic factor in patients with R/R DLBCL undergoing CAR-T cell therapy.

Neoantigen vaccines hold great promise in cancer immunotherapy, but the comparative efficacy of different vaccine platforms, particularly in the context of tumor burden (TB), remains insufficiently studied. In this research, we evaluated the safety and therapeutic efficacy of synthetic long peptide and mRNA-based vaccines, both designed to target identical neoantigens across different Lewis Lung Carcinoma (LLC) tumor burdens. We employed the LLC syngeneic mouse model, a widely used preclinical model for aggressive and immunosuppressive tumors. Our findings demonstrated that the mRNA-based vaccine significantly outperformed the peptide-based vaccine in preventing tumor growth in mice with low TB. These results underscore the potential of mRNA vaccines as a more effective approach for treating aggressive tumors, contributing valuable insights for the future development of neoantigen-based cancer vaccines.

Head and neck squamous cell carcinoma (HNSCC) presents a significant therapeutic challenge because of the limited effectiveness of current treatments including immunotherapy and chemotherapy. This study investigated the potential of a novel combination therapy using allogeneic natural killer (NK) cells and cetuximab, an anti-epidermal growth factor receptor monoclonal antibody, to enhance anti-tumor efficacy in HNSCC. Allogeneic NK cells were tested against HNSCC cells in vitro and NOG (NOD/Shi-scid/IL-2Rγ null) xenograft mouse models for cytotoxicity. In vitro assays demonstrated enhanced cytotoxicity against HNSCC cells when NK cells were combined with cetuximab, a phenomenon attributed to antibody-dependent cellular cytotoxicity. In vivo, the combination therapy exhibited a significant anti-tumor effect compared to either monotherapy, with high NK cell infiltration and cytotoxic activity in the tumor microenvironment. Tumor infiltration by NK cells was confirmed using flow cytometry and immunohistochemistry, highlighting the increased presence of NK cells (CD3^- CD56⁺). These findings suggest that combination allogeneic NK cells and cetuximab could be a potential therapeutic modality for HNSCC and provide a foundation for future clinical trials to improve patient outcomes.

Tumor cells can evade antitumor immune response by expressing the PD-L1 ligand, leading to the inhibition of PD-1-expressing T lymphocytes. The mechanisms that regulate PD-L1 expression in cancer cells are imperfectly characterized. The transcription factor ZEB1, a major regulator of phenotype switching in melanoma cells, was shown to promote immune escape in melanoma by repressing T cell infiltration. Using inducible models of phenotype switching and ZEB1 gain/loss-of-function melanoma, we show that ZEB1 binds to the CD274 (PD-L1) promoter, directly enhancing PD-L1 mRNA transcription and its expression at the cell membrane. Furthermore, using single-cell spatial analyses on human primary melanoma samples, we demonstrate the correlation of ZEB1 and PD-L1 expression in tumor cells. Overall, these data identify ZEB1-mediated regulation of PD-L1 tumor expression as a mechanism that could contribute to immune escape in melanoma.

Immunotherapy holds significant promise for treating head and neck squamous cell carcinoma (HNSCC), yet responses are limited to a subset of patients. This research investigates whether analyzing the peripheral T-cell receptor (TCR) repertoire could help identify patients who are more likely to benefit from a combination treatment of cetuximab and nivolumab. We report here updated correlative analysis using all samples profiled with deep immunoSEQ assay to study the peripheral TCR repertoires in peripheral blood mononuclear cells from patients enrolled in a phase I/II trial (NCT03370276). TCR repertoires were analyzed in 67 patients. Of these, 64 had available baseline data. Overall, our findings confirm that a more polyclonal peripheral TCR repertoire is associated with improved response to concurrent cetuximab and nivolumab in HNSCC. While the baseline productive Simpson clonality did not reach statistically significant differences in response groups, significant differences were observed within the HPV-negative subgroup and among patients who had received previous ICI therapy. Additionally, the TCR diversity at baseline and early follow-up was associated with overall survival. TRBV/TRBJ gene usage analysis also identified specific gene pairs associated with patient outcomes. Furthermore, our analysis indicates that the TCR clonality patterns are modulated by prior treatment exposures and tumor HPV status, suggesting a cohort expansion within these subgroups for further validation. Together, this study demonstrates the feasibility of leveraging the peripheral T-cell repertoire profiling and clonality dynamics as predictive biomarkers for immunotherapy efficacy in HNSCC.