Platelets in the tumor microenvironment: potential mediators of immune exclusion and resistance to immune checkpoint inhibitor therapy.

BackgroundThe development of immune checkpoint inhibitor (ICI) therapy has fundamentally changed the landscape of cancer treatment. While ICIs have exhibited remarkable efficacy across diverse cancer types, the majority of cancer...

BackgroundImmune checkpoint inhibitors have traditionally been understood to exert their effects primarily within the tumor microenvironment, particularly targeting CD8 + T cells. However, recent studies have highlighted a pivotal role of tumor-draining lymph nodes in mediating responses to immune checkpoint inhibitor therapy. This study aimed to elucidate the specific mechanisms by which tumor-draining lymph nodes respond to immune checkpoint inhibitor therapy and regulate the tumor microenvironment in human colorectal cancer.MethodsWe performed single-cell RNA sequencing and T cell receptor sequencing on tumor-draining lymph nodes and tumor tissues from patients with colorectal cancer. Through in-depth analysis of the single-cell data, we established the connection between TDLNs and tumor, and explored the impact of immune checkpoint inhibitor therapy on the immune microenvironment of tumor-draining lymph nodes. In addition, we conducted animal experiments to validate these findings.ResultsOur findings revealed that immune checkpoint inhibitor treatment induced the expansion of tumor-specific CD8 + effector memory T cells within tumor-draining lymph nodes, which may serve as a source for the progenitor-exhausted CD8 + T cells in the tumor microenvironment. Moreover, conventional dendritic cells type 1 and macrophages within tumor-draining lymph nodes facilitated this process. We also observed that immune checkpoint inhibitor therapy promoted the expansion of tumor-specific CD4 + follicular helper T cells in tumor-draining lymph nodes, which may explain the increase of CD4 + follicular helper T cells in the tumor microenvironment after immune checkpoint inhibitor therapy. These hypotheses were corroborated through experiments in mice.ConclusionsOur findings delineate the critical regulatory function of tumor-draining lymph nodes in modulating the tumor microenvironment during Immune checkpoint inhibitor therapy.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00262-025-04187-w.

although MMR-D may be surrogate of immune checkpoint inhibitors in most of the solid tumors, this response is not independent of disease biology, which appears to lead to distinct outcomes across different types of cancers.

The Philadelphia chromosome-negative (Ph-) myeloproliferative neoplasms (MPNs), which include essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are enduring and well-known conditions. These disorders are characterized by the abnormal growth of one or more hematopoietic cell lineages in the body's stem cells, leading to the enlargement of organs and the manifestation of constitutional symptoms. Numerous studies have provided evidence indicating that the pathogenesis of these diseases involves the dysregulation of the immune system and the presence of chronic inflammation, both of which are significant factors. Lately, the treatment of cancer including hematological malignancy has progressed on the agents aiming for the immune system, cytokine environment, immunotherapy agents, and targeted immune therapy. Immune checkpoints are the molecules that regulate T cell function in the tumor microenvironment (TME). The first line of primary immune checkpoints are programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte antigen-4 (CTLA-4). Immune checkpoint inhibitor therapy (ICIT) exerts its anti-tumor actions by blocking the inhibitory pathways in T cells and has reformed cancer treatment. Despite the impressive clinical success of ICIT, tumor internal resistance poses a challenge for oncologists leading to a low response rate in solid tumors and hematological malignancies. A Phase II trial on nivolumab for patients with post-essential thrombocythemia myelofibrosis, primary myelofibrosis, or post-polycythemia myelofibrosis was performed (Identifier: NCT02421354). This trial tested the efficacy of a PD-1 blockade agent, namely nivolumab, but was terminated prematurely due to adverse events and lack of efficacy. A multicenter, Phase II, single-arm open-label study was conducted including pembrolizumab in patients with primary thrombocythemia, post-essential thrombocythemia or post-polycythemia vera myelofibrosis that were ineligible for or were previously treated with ruxolitinib. This study showed that pembrolizumab treatment did not have many adverse events, but there were no pertinent clinical responses hence it was terminated after the first stage was completed. To avail the benefits from immunotherapy, the paradigm has shifted to new immune checkpoints in the TME such as lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin domain 3 (TIM-3), T cell immunoglobulin and ITIM domain (TIGIT), V-domain immunoglobulin-containing suppressor of T cell activation (VISTA), and human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) forming the basis of next-generation ICIT. The primary aim of this article is to underscore and elucidate the significance of next-generation ICIT in the context of MPN. Specifically, we aim to explore the potential of monoclonal antibodies as targeted immunotherapy and the development of vaccines targeting specific MPN epitopes, with the intent of augmenting tumor-related immune responses. It is anticipated that these therapeutic modalities rooted in immunotherapy will not only expand but also enhance the existing treatment regimens for patients afflicted with MPN. Preliminary studies from our laboratory showed over-expressed MDSC and over-expressed VISTA in MDSC, and in progenitor and immune cells directing the need for more clinical trials using next-generation ICI in the treatment of MPN.

Cutaneous adverse events to immune checkpoint inhibitors in pediatric populations: A retrospective cohort study

Background: Reversal of CD8 T-cell exhaustion was considered a major antitumor mechanism of anti-programmed cell death-1 (PD-1)/ anti-programmed death ligand-1 (PD-L1)-based immune checkpoint inhibitor (ICI) therapy. Objectives: The aim of this study was to identify markers of T-cell exhaustion that is best associated with ICI treatment efficacy for advanced hepatocellular carcinoma (HCC). Methods: Immune cell composition of archival tumor samples was analyzed by transcriptomic analysis and multiplex immunofluorescence staining. Results: HCC patients with objective response after anti-PD-1/anti-PD-L1-based ICI therapy (n = 42) had higher expression of genes related to T-cell exhaustion. A 9-gene signature (LAG3, CD244, CCL5, CXCL9, CXCL13, MSR1, CSF3R, CYBB, and KLRK1) was defined, whose expression was higher in patients with response to ICI therapy, correlated with density of CD8⁺LAG3⁺ cells in tumor microenvironment, and independently predicted better progression-free and overall survival. This 9-gene signature had similar predictive values for patients who received single-agent or combination ICI therapy and was not associated with prognosis in HCC patients who received surgery, suggesting that it may outperform other T-cell signatures for predicting efficacy of ICI therapy for HCC. For HCC patients who underwent surgery for both the primary liver and metastatic lung tumors (n = 31), lung metastatic HCC was associated with a higher exhausted CD8 T-cell signature, consistent with prior observation that patients with lung metastatic HCC may have higher probability of response to ICI therapy. Conclusions: CD8 T-cell exhaustion in tumor microenvironment may predict better efficacy of ICI therapy for HCC.

e20630 Background: Immune checkpoint inhibitor (ICI) therapy is a cornerstone in the treatment of metastatic non-small cell lung cancer (NSCLC). However, many patients develop resistance or fail to respond to ICI. There has been a lot of interest in studying the host factors that might influence the response to immunotherapy. In recent years, the Obesity paradox phenomenon has been studied in multiple cancers. However, there is scarce information on the impact of obesity on the various ICI therapies on NSCLC patients in the US. In this study, we are presenting the first real-world analysis of the effect of obesity on survival in US based patients diagnosed with metastatic NSCLC and receiving ICIs. We also tried to unveil any possible underlying mechanisms that might explain this phenomenon like complications and immune‐related adverse events (irAEs). Methods: Data was retrospectively collected from the independent US population-based TriNetX network, a national electronic health record database with 120 million US patients from over 70 healthcare organizations. We identified patients ≥ 18 years old with non-small cell lung cancer diagnosis who received ICI therapy between 2012 and 2024. ICI therapies included pembrolizumab, nivolumab, atezolizumab, durvalumab, ipilimumab and cemiplimab. Patients were then split into two cohorts: those with normal BMI (18.5-24.9) and obese BMI (≥30). Patients were then 1:1 propensity score matched based on age, sex, race, ethnicity, type of ICI therapy used, comorbidities and staging. Overall survival (OS), NSCLC related complications and irAEs were measured at 6 months, 1 year and 3 years after initiation of ICI treatment. Results: We identified 10,056 patients over the age of 18 who received ICI therapy for NSCLC. After 1:1 matching, each cohort in our analysis included 2762 patients. In the normal and obese groups mean age in both groups was 66.2 ± 10.8 and 66.3 ± 9.69 years respectively. Patients were also more likely to be white (73%) and male (49%) in both groups. Obesity BMI was associated with significantly improved OS at 6 months (hazard ratio [HR], 0.78 [95% CI, 0.66-0.83]), 1 year (HR, 0.81 [95% CI, 0.74-0.89]), and 3 years (HR, 0.88 [95% CI, 0.81-0.95]) after ICI treatment, compared with patients with normal BMI. There was no difference in rates of NSCLC specific complications or irAEs at any of the time points from 6 months to 3 years. Conclusions: Analysis of one of the largest US based databases showed that obesity is associated with better overall survival without significant difference in complications or irAEs which suggest that the difference in the survival is likely due to the direct effect of the obesity on the cancers. Further clinical trials and transitional studies should be geared towards investigating the effects of obesity on tumor microenvironment.

Atypical Antiglomerular Basement Membrane Nephritis Following Immune Checkpoint Inhibitor

BackgroundUnderstanding the dynamics of immune cells in the lung tumor microenvironment following immune checkpoint inhibitor (ICI) therapy is important for developing therapies tailored to patients with progressive disease. We sought...

Combining radiation with immune checkpoint inhibitors therapy for HCC: From the alteration of the immune microenvironment by radiotherapy

Cholangiocarcinoma represents an aggressive malignancy with poor prognosis, particularly for intrahepatic Cholangiocarcinoma. Despite recent advancements in chemotherapy and immune checkpoint blockade therapies, survival outcomes remain suboptimal. A key obstacle in treating Cholangiocarcinoma is its immune exclusion and resistance to Cholangiocarcinoma, which is influenced by metabolic reprogramming within the tumor microenvironment. This review explores the dual control of metabolism and immunity in Cholangiocarcinoma, highlighting the intricate interplay between metabolic pathways (e.g., glycolysis, lactate accumulation, fatty acid oxidation) and immune evasion mechanisms. We examine how bile acid signaling, hypoxia, and stromal interactions shape Cholangiocarcinoma’s immune landscape, facilitating tumor progression and immune resistance. Moreover, we discuss emerging therapeutic strategies that target metabolic vulnerabilities to “convert” immune-excluded Cholangiocarcinoma into a more immunologically responsive state. These strategies include metabolic inhibitors targeting lactate, amino acid catabolism, and fatty acid metabolism, as well as approaches to modulate bile acid signaling. We propose that combining metabolic reprogramming with immune checkpoint blockade therapies holds significant promise in enhancing immune responses and improving therapeutic outcomes for Cholangiocarcinoma patients. This review provides a comprehensive framework for future research and clinical trials, aiming to bridge the gap between metabolic insights and immunotherapy in Cholangiocarcinoma treatment.

The Inhibitory PVRL1/PVR/TIGIT Axis in Immune Therapy for Hepatocellular Carcinoma

e14610 Background: Immune checkpoint inhibitors represent an important advance in cancer therapeutics. However, most cancer patients do not respond or become resistant to this form of immune therapy. Methods: We evaluated the ability of Ad-p53 to reverse immune checkpoint inhibitor resistance and induce abscopal effects in the immune therapy resistant murine B16F10 melanoma tumor model. To mimic clinical conditions of checkpoint inhibitor resistance, animals with established tumors were treated with anti-PD-1 before initiating Ad-p53 intra-tumoral therapy. Results: Anti-PD-1 had minimal therapeutic efficacy compared to control treatment. A statistical analysis of variance (ANOVA) comparison of tumor volumes revealed that the combined effect of Ad-p53 and anti-PD-1 treatment was synergistic and superior to either therapy alone (p = 0.0001). Surprisingly, there was a statistically significant abscopal effect with decreased growth of contralateral tumors not injected with Ad -p53. The Ad- p53 alone (p = 0.046) and Ad- p53 + anti-PD-1 (p = 0.0243) treatment groups both demonstrated a statistically significant decreased abscopal tumor growth compared to treatment with anti-PD-1 alone. Combined Ad- p53 and anti-PD-1 therapy demonstrated a statistically significant increase in survival compared to Ad- p53 therapy alone (p = 0.0167) and anti-PD-1 therapy alone (p < 0.001) by the log rank test. We have initiated a Phase 1 clinical trial of Ad-p53 intra-hepatic arterial therapy in combination with capecitabine for patients with solid tumor liver metastases. In the first cohort of patients at a dose of 2 x 1012viral particles, treatment has been well tolerated with transient fever, chills and rigors. In one patient, decreased SUV uptake on PET scans of distant lymph node metastases suggested possible abscopal effects. Conclusions: These results suggest that Ad-p53 tumor suppressor immune gene therapy may reverse immune checkpoint inhibitor resistance and induce abscopal effects supporting the planned clinical evaluation of combined Ad-p53 and anti-PD-1 therapy in patients resistant to immune checkpoint inhibitor therapy. Clinical trial information: NCT02842125.

Novel patented markers of immune checkpoint inhibitor efficacy.

IntroductionN6-methyladenosine (m6A) modification and long non-coding RNAs (lncRNAs) play pivotal roles in the progression of hepatocellular carcinoma (HCC). However, how their interaction is involved in the prognostic value of HCC and immune checkpoint inhibitors (ICIs) therapy remains unclear.MethodsThe RNA sequencing and clinical data of HCC patients were collected from TCGA database. The prognostic m6A-related lncRNAs were screened out with Pearson correlation test, univariate Cox analysis and least absolute shrinkage and selection operator (LASSO) Cox regression. Patients with HCC were classified into 2 subtypes by consensus clustering. Survival analyses were performed to assess the prognostic value of different clusters and risk models. Potential tumor correlated biological pathways correlated with different clusters were explored through gene set enrichment analysis. We also identified the relationship of the risk model and clusters with response to immune checkpoint inhibitors (ICIs) therapy and tumor microenvironment (TME). Furthermore, the prognostic value of the 9 m6A-related lncRNAs was validated in the external cohort. Finally, the role of SNHG4 was explored by silencing and overexpression of SNHG4 through conducting proliferation, migration and invasion experiments.ResultsPatients from 2 clusters and different risk groups based on m6A-related lncRNAs had significantly different clinicopathological characteristics and overall survival outcomes. Tumor-correlated biological pathways were found to be correlated with Cluster 2 through GSEA. Moreover, we found that patients from different clusters and risk groups expressed higher levels of immune checkpoint genes and had distinct TME and different responses for ICIs therapy. Prognostic value of this risk model was further confirmed in the external cohort. Finally, consistent with the discovery, SNHG4 played an oncogenic role in vitro.ConclusionOur study demonstrated that the 9 m6A-related lncRNA signature may serve as a novel predictor in the prognosis of HCC and optimize (ICIs) therapy. SNHG4 plays an oncogenic role in HCC.