Search Results (395)

Feline mammary carcinoma (FMC) exhibits aggressive behavior, with limited treatment options. Given the relevance of the PD-1/PD-L1/PD-L2 axis in human breast cancer immunotherapy, this study assessed PD-1 and its ligands in rare FMC histotypes (n = 48) using immunohistochemistry on tumor cells (TCs), intratumoral lymphocytes (iTILs), and stromal tumor-infiltrating lymphocytes (sTILs). PD-1 was expressed in 13% of TCs, 85% of iTILs, and 94% of sTILs, while PD-L1 was observed in 46% of TCs, 96% of iTILs, and 100% of sTILs. PD-L2 was expressed in 79% of TCs and 100% of both iTILs and sTILs, with PD-L1/PD-L2 co-expression in 42% of TCs. Higher PD-1 IHC scores in TCs were associated with a less aggressive biological behavior; PD-L1 in iTILs was linked to skin ulceration, whereas PD-L2 in TCs was associated with its absence. Our findings highlight the relevance of the PD-1/PD-L1/PD-L2 immune checkpoint in rare FMC subtypes and support further investigation into checkpoint-blockade therapies. Full article

Gastrointestinal (GI) malignancies are diverse and particularly challenging in terms of current immunotherapy but hold great opportunity for impact given that they constitute the highest cancer incidence and mortality rates worldwide. Traditional treatment options for solid GI malignancies include surgical intervention, chemotherapy, radiation, or a combination of these treatments. Emerging modalities within immunotherapy are anticipated to extend the results with conventional therapy by stimulating the patient’s own intrinsic potential for tumor-specific immunologic rejection. Combination regimens of chemotherapy and tumor-infiltrating lymphocyte (TIL) therapy in advanced colorectal cancer and pancreatic cancer, autologous monocyte therapy in advanced gastric cancer, and CAR-T therapy trained against GI-selective tumor antigens such as carcinoembryonic antigen are currently being studied. Clinical trials are underway to study the combination of various chemotherapeutic agents along with immunotherapy in the management of cholangiocarcinoma, hepatocellular carcinoma, and esophageal cancer. Alternative therapies are needed based on the tumor immune microenvironment, which can lead to a personalized approach to treatment. In this review, we discuss the current status of various modalities of immunotherapy in common GI malignancies, along with their mechanisms of immune activation and cancer suppression. We will also discuss the use of immunotherapy in less common solid GI malignancies and touch on recent advancements and clinical trials. Full article

Cancer is no longer considered as an isolated event. Rather, it occurs because of a complex biological drive orchestrating different cell types, growth factors, cytokines, and signaling pathways within the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are the most populous stromal cells within the complex ecosystem of TME, with significant heterogeneity and plasticity in origin and functional phenotypes. Very enigmatic cells, CAFs determine the progress and outcomes of tumors through extensive reciprocal signaling with different tumors infiltrating immune cells in the TME. In their biological drive, CAFs release numerous chemical mediators and utilize various signaling pathways to recruit and modulate tumor-infiltrating immune cells. The CAF-induced secretome and exosomes render immune cells ineffective for their antitumor activities. Moreover, by upregulating immune inhibitory checkpoints, CAFs create an immunosuppressive TME that impedes the susceptibility of tumor cells to tumor-infiltrating lymphocytes (TILs). Further, by depositing and remodeling extracellular matrix (ECM), CAFs reshape the TME, which enhances tumor growth, invasion, metastasis, and chemoresistance. Understanding of CAF biology and its crosstalk with tumor-infiltrating immune cells is crucial not only to gain insight in tumorigenesis but to optimize the potential of novel targeted immunotherapies for cancers. The complex relationships between CAFs and tumor-infiltrating immune cells remain unclear and need further study. Herein, in this narrative review we have focused on updates of CAF biology and its interactions with tumor-infiltrating immune cells in generating immunosuppressive TME and resistance to cell death. Full article

Lifileucel, a tumor-infiltrating lymphocyte (TIL) cell therapy approved for advanced melanoma, demonstrates promise for treating other solid tumors, including endometrial cancer (EC). The current study evaluates the feasibility of manufacturing TILs from EC tumors using Iovance’s proprietary 22-day Gen2 manufacturing process. Key parameters, including TIL yield, viability, immune phenotype, T-cell receptor clonality, and cytotoxic activity, were assessed. Of the 11 EC tumor samples processed at research scale, 10 (91%) successfully generated >1 × 10⁹ viable TIL cells, with a median yield of 1.1 × 10¹⁰ cells and a median viability of 82.8%. Of the four EC tumor samples processed at full scale, all achieved the pre-specified TVC and viability targets. Putative tumor-reactive T-cell clones were maintained throughout the manufacturing process. Functional reactivity was evidenced by the upregulation of 4-1BB in CD8+ T cells, OX40 in CD4+ T cells, and increased production of IFN-γ and TNF-α upon autologous tumor stimulation. Furthermore, antitumor activity was confirmed using an in vitro autologous tumor organoid killing assay. These findings demonstrate the feasibility of ex vivo TIL expansion from EC tumors. This study provides a rationale for the initiation of the phase II clinical trial IOV-END-201 (NCT06481592) to evaluate lifileucel in patients with advanced EC. Full article

Background/Objectives: This review discusses the resistance mechanisms in the tumor microenvironment (TME) of malignant melanoma that disrupt the efficacy of immune checkpoint inhibitors (ICIs). In this review, we focus on the roles of immune cells, including tumor-infiltrating lymphocytes (TILs), macrophages, dendritic cells, and other signaling pathways. We explore the interplay between innate and adaptive immunity in the TME and tumor intrinsic resistance mechanisms, such as β-catenin, which has future implications for the usage of ICIs in patients with therapy-resistant tumors. Methods: A total of 1052 studies were extracted from the PubMed database searching for keywords and phrases that included [melanoma AND immune checkpoint inhibitor resistance]. After a title/abstract and full-text review, 101 studies were identified that fit the inclusion/exclusion criteria. Results: Cancer-associated fibroblasts (CAFs), M2 macrophages, and myeloid-derived suppressor cells (MDSCs) are significant in remodeling the TME to promote melanoma growth. Melanoma resistance to ICIs is complex and involves TME alterations, tumor intrinsic factors, and immune evasion. Key components of resistance include reduced CD8+ T cell infiltration, decreased host immune response, and immunosuppressive cytokines. Conclusions: Predictive biomarkers and specific models are the future of individualized melanoma management and show great promise in their approach to targeted therapy production. Tumor profiling can be utilized to help predict the efficacy of ICIs, and specific biomarkers predicting therapy responses are instrumental in moving towards personalized and more efficacious medicine. As more melanoma resistance emerges, alternative and combinatorial therapy based on knowledge of existing resistance mechanisms will be needed. Full article

Endometrial carcinoma (EC) is the most common gynaecological malignancy in developed nations, exhibiting significant molecular heterogeneity that impacts prognosis and treatment response, particularly in advanced or recurrent settings. Traditional classification is increasingly supplemented by molecular subtyping (POLE-ultramutated, MSI-high/dMMR, NSMP, p53-mutated/CNH), which provides crucial prognostic information and predicts benefit from immunotherapy. This review summarizes the landscape of predictive biomarkers for immune checkpoint inhibitor (ICI) therapy in EC, emphasizing a new therapeutic scenario for advanced and recurrent EC. Mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H), leading to high tumor mutational burden (TMB) and increased neoantigen production, is the most established predictor, resulting in FDA approvals for pembrolizumab and dostarlimab in this subgroup. POLE mutations also confer hypermutation and high immunogenicity, predicting a favorable ICI response. Other biomarkers, including PD-L1 expression and TMB, show variable correlation with response and require further standardization. The tumor immune microenvironment, including tumor-infiltrating lymphocytes (TILs), also influences treatment outcomes. Clinical trials have demonstrated significant survival benefits for ICIs combined with chemotherapy (e.g., dostarlimab/pembrolizumab + carboplatin/paclitaxel) in first-line settings, especially for dMMR/MSI-H EC, and for ICI combinations with targeted agents (e.g., lenvatinib + pembrolizumab) in previously treated patients. Integrating molecular classification and validated biomarkers is essential for optimizing patient selection and developing personalized immunotherapy strategies for EC. Full article

Cutaneous melanoma is an aggressive cancer with an increasing incidence worldwide, highlighting the need for research into its pathogenesis. The tumor microenvironment (TME) plays a critical role in melanoma progression and consists of cellular components and an extracellular matrix (ECM) rich in cytokines and signaling molecules. The most abundant stromal cells within the TME are cancer-associated fibroblasts (CAFs), which remodel the ECM and modulate immune responses. Among immune cells, tumor-associated macrophages (TAMs) predominate, and their polarization toward the M2 phenotype supports tumor progression. Tumor-infiltrating lymphocytes (TILs) have diverse functions, including cytotoxic T-cells, helper T-cells that modulate immune response, B-cells forming tertiary lymphoid structures (TLS), and regulatory T-cells with immunosuppressive properties. Dendritic cells (DCs) also play a complex role in the TME. A notable subpopulation are mature regulatory dendritic cells (mregDCs), which contribute to immune evasion. All of these TME components may drive tumorigenesis. Advancements in melanoma treatment—including immunotherapy and targeted therapies—have significantly improved outcomes in advanced-stage disease. In parallel, emerging approaches targeting the tumor microenvironment and gut microbiome, as well as personalized strategies such as neoantigen vaccines and cell-based therapies, are under active investigation and may further enhance therapeutic efficacy in the near future. Full article

Background/Objectives: Tumor-infiltrating lymphocytes (TILs) and inflammation status are emerging prognostic markers in various cancers, but their significance in high-grade serous ovarian carcinoma (HGSC) remains unclear. Our objective was to evaluate different TIL subtypes and inflammation status in relation to progression-free survival (PFS) in primary HGSC. Methods: CD3⁺/CD4⁺/CD8⁺/PD-1+ stromal TILs (sTILs) and intraepithelial TILs (iTILs) were evaluated by manual assessment and digital image analysis (DIA), following TIL Working Group recommendations. Inflammation status was evaluated through the following scores: systemic immune-inflammation index (SII), pan-immune-inflammation value (PIV), CA125, and lactate dehydrogenase (LDH). Results: CD8⁺ TILs were the most prevalent subtype in both iTILs and sTILs. However, sTILs were significantly more abundant than iTILs (p < 0.001) among all subsets, except for PD-1+ cells. DIA results of TIL assessments were in agreement with manual assessments. High stromal CD3⁺ and CD8⁺ TILs, PIV, CA125, and LDH, were associated with improved PFS. Potential independent prognostic factors for PFS in manual assessment were PIV (HR = 0.32, CI 95% = 0.12–0.82) and CD8⁺ sTILs (HR = 0.30, CI 95% = 0.12–0.79), whereas in DIA assessment they were CD3⁺ sTILs (HR = 0.31, CI 95% = 0.15–0.67), PIV (HR = 0.35, 95% CI 0.13–0.96), and residual disease (HR = 0.21 95% CI 0.08–0.53). Conclusions: CD3⁺/CD8⁺ sTILs and PIV are promising prognostic indicators in HGSC; however, further research is needed to confirm their clinical utility. Full article

Gliomas, particularly IDH-wildtype ones, are associated with poor prognosis, yet their immunological landscape remains uncertain. We analyzed RNA sequencing data from 55 glioma patients, estimating immune infiltration with CIBERSORTx and immune cell states via Ecotyper. IDH-wildtype gliomas showed significantly higher immune cell infiltration (p = 0.002), notably of regulatory T cells (Tregs) and macrophages, and a greater proportion of exhausted T cells compared to IDH-mutant gliomas. Clustering based on immune profiles revealed two groups. Cluster A, enriched for IDH-wildtype cases, exhibited heightened immune infiltration but also marked immunosuppression. Cluster B, which included both IDH-wildtype and mutant cases, showed lower levels of immune infiltration. Tumor-infiltrating lymphocyte (TIL) cultured from IDH-wildtype tumors demonstrated limited expansion following anti-PD-1, a CSF1R inhibitor, or a STAT3 inhibitor treatment, without clear cluster-specific differences. Tumor-reactive TILs were mainly observed in cluster A. These findings highlight that IDH-wildtype gliomas have an immunosuppressive and heterogeneous microenvironment, potentially limiting responses to single-agent immunotherapies. A personalized, multi-targeted approach addressing multiple immunosuppressive mechanisms may be essential to improve immunotherapy outcomes in this aggressive glioma subgroup. Full article

Triple-negative breast cancer (TNBC) is a heterogenous group of breast tumors. This type of breast tumor is relatively difficult to manage, due to the lack of expression of Hormone Receptors (HR) and human epidermal growth factor receptor (HER2). Efforts have been made to understand the factors involved in determining how a triple-negative breast tumor responds to therapy. The standard of treatment in most cases today is a combined modality of immune checkpoint inhibitors (ICIs) and chemotherapy with agents such as anti-mitotic (taxanes) or DNA-damaging agents (alkylating agents, cyclophosphamides, platin salts). In this study, we investigated the predictive and prognostic factors for TNBC, in the neoadjuvant setting; understanding each patient’s response before treatment initiation is crucial to guiding the subsequent approach and finally improving patient outcomes. We focused on tumor-infiltrating lymphocytes at the site of the primary tumor (TILs), circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), the mutational status of protein 53 (p53), and Ki-67, investigating the potential roles of these factors in predicting responses to anti-cancer agents. Full article

Immune checkpoint inhibition is a cornerstone of bladder cancer therapy, but its efficacy in non-urothelial subtypes of bladder cancer is limited, and the prognosis remains poor. Therefore, we investigated the potential of the immune checkpoint molecules TIM-3, TIGIT, and LAG-3 in squamous-cell carcinoma (SCC) and adenocarcinoma (ADENO) of the urinary bladder. Tumor-infiltrating lymphocytes (TILs) showed a high expression of TIM-3 and TIGIT in both SCC and ADENO, while LAG-3-positive TILs were absent in ADENO and present in 46% of SCC. Quantitative analysis revealed age-independent expression of TIM-3 in SCC (r = −0.001, p = 0.997) and ADENO (r = 0.135, p = 0.549), with increasing age correlating with higher expression of TIGIT (r = 0.157, p = 0.242) and LAG-3 (0.106, p = 0.436) in the SCC cohort and of TIGIT (r = 0.276, p = 0.214) in the ADENO cohort. Male patients showed increased TIGIT scores in ADENO (p < 0.01). Of note, a high infiltration of TIM-3-TILs (p = 0.048) correlated with worse progression-free survival in SCC. These results highlight the differential expression of co-inhibitory receptors in non-urothelial bladder cancer subtypes and provide preclinical evidence for new therapeutic targets. Biomarker testing prior to clinical trials is essential for identifying the most suitable patients for targeted immunotherapy. Full article

Introduction: The limited value of TNM staging in locally advanced (LA) nasopharyngeal carcinoma (NPC), defined as stage III or IV NPC, highlights the need for prognostic markers. Here, we aimed to evaluate the ability of the cancer stem cell markers, BMI1, ALDH1, CD44, and CD24, and the epithelial–mesenchymal transition marker, vimentin, as novel prognostic markers in LA-NPC. Methods: A cohort of 83 patients with LA-NPC, previously recruited for another trial with a different goal, was used. The marker expression in tissue sections was evaluated using immunohistochemistry, and the association of expression with survival outcomes was analyzed using the Kaplan–Meier method and Cox regression analysis. Results: The expression of BMI1 and ALDH1 was not associated with survival. The tumoral expression of CD24, CD44, and vimentin was significantly associated with disease-free survival (DFS), whereas only the expression of CD24 was also significantly associated with overall survival (OS). Indeed, CD24 expression emerged as an independent prognostic factor as it was associated with survival in univariate and multivariate Cox regression analysis. Interestingly, combining the status of CD24 expression in tumor cells with the density of CD3⁺ tumor-infiltrating lymphocytes (TIL), a microenvironment/immune-related marker, identified a high-risk subgroup with the worst DFS and OS. Conclusions: These results suggest the utility of combining tumoral CD24 expression and the CD3⁺ TIL density as a prognostic factor in LA-NPC, with potential application in disease management and future trial design. Our findings also highlight the potential of combining immune- and cancer stem cell-related factors in personalized treatment strategies for cancer. Full article

UL16-binding protein 2 (ULBP2), a ligand for the activating receptor NKG2D, plays a dual role in tumor immunity, promoting immune activation or suppression, depending on the context. To investigate its impact on CD4⁺CD25⁺ T cell-targeted immunotherapies, we used a syngeneic CT26 colon cancer model engineered to express ULBP2 and compared tumor growth and tumor-infiltrating lymphocyte (TIL) profiles in control and ULBP2-expressing tumors treated with anti-CD4, anti-CD25, or anti-CTLA-4 antibodies. Tumor growth was uniformly assessed on day 21 post-transplantation, and TIL analysis was performed in groups with evaluable residual tumors. Anti-CD4 antibody significantly suppressed tumor growth in mock-transfected tumors, while no significant suppression was observed in ULBP2-expressing tumors. Anti-CD25 antibody had limited efficacy in mock tumors and tended to promote tumor growth in ULBP2-expressing tumors. Following these treatments, ULBP2 expression was associated with reduced NKG2D expression in CD8⁺ effector memory T cells, particularly PD-1^high subsets. In contrast, anti-CTLA-4 antibody treatment induced marked tumor regression irrespective of ULBP2 expression. These findings suggest that ULBP2–NKG2D signaling may contribute to altered CD8⁺ T cell phenotypes under T cell-modulatory conditions, potentially impacting the outcome of CD4⁺CD25⁺ T cell-targeted therapies and providing insights for optimizing immunotherapeutic strategies. Full article

Background/Objectives: Adenocarcinomas of the esophagogastric and gastric areas are often managed with a multimodal treatment including neoadjuvant chemotherapy and surgery. The impact of neoadjuvant chemotherapy on the host’s antitumoral immune response remains largely unknown. Methods: A retrospective review of a single-institution cohort of patients with adenocarcinoma of the stomach or esophagogastric area undergoing curative intent surgery after neoadjuvant chemotherapy FLOT (Fluorouracil, Leucovorin, Oxaliplatin, Docetaxel) was reviewed. After institutional ethics approval, pathologic slides were re-reviewed and tumor-infiltrating lymphocyte scores were calculated. Tumor-infiltrating lymphocytes (TILs) were studied in conjunction with tumor regression scores (TRG) and the degree of regression in the involved lymph nodes as well as in correlation with the lymph node ratio (the ratio of involved lymph nodes over the total number of lymph nodes resected). Results: A total of 106 patients were reviewed. No statistical correlation could be established between the tumor-infiltrating lymphocyte scores and the degree of regression in the primary tumor as well as with the partial response to chemotherapy of pathologically involved lymph nodes. The TIL score also did not correlate with the lymph node ratio in our patient cohort. A strong correlation was noted between TILs and lymph nodes that completely regressed after neoadjuvant chemotherapy. Conclusions: Tumor-infiltrating lymphocytes do not correlate with the response of the primary tumor or the partial response of the involved lymph nodes, but only with the complete response to neoadjuvant chemotherapy of tumor-involved lymph nodes. Our study focuses on the effects of neoadjuvant chemotherapy on tumor-infiltrating lymphocytes compared to the effects on the primary tumor and the involved lymph nodes. Full article

Introduction: A potential prognostic biomarker for predicting the response to immunotherapy in breast cancer (BC) is tumor-infiltrating lymphocytes (TILs). The purpose of this research is to examine if preoperative characteristics of breast magnetic resonance imaging (MRI) may be used to predict TIL levels in a group of BC patients. In addition, we aimed to assess any potential relationship between the various tumor biology subgroups and MR imaging characteristics. Materials and Methods: This retrospective analysis comprised 145 participants with histologically confirmed BC who had preoperative DCE MRI. We collected and examined patient information as well as tumor MRI features, such as size and shape, edema, necrosis, multifocality/multicentricity, background parenchymal enhancement (BPE), and apparent diffusion coefficient (ADC) values. We divided patients into two groups based on their TIL levels: low-TIL (<10%) and high-TIL groups (≥10%). Following core needle biopsy, tumors were categorized as Luminal A, Luminal B, HER2+, and Triple Negative using immunohistochemical analysis. TIL levels were correlated with tumor biological profiles and MRI features using both parametric and non-parametric tests. Results: Patients were categorized as having a high TIL level (≥10%; 54/145 patients) and a low TIL level (<10%; 91/145 patients) based on the median TIL level of 10%. Of the lesions, 13 were HER2-positive, 16 were Triple Negative, 49 were Luminal A, and 67 were Luminal B. Higher TIL levels were statistically correlated with TNBC (11/16 individuals, p: 0.007). ADC values (p = 0.01), BPE levels (p = 0.008), and TIL levels were all significantly negatively correlated. Significantly more homogenous enhancement was seen in tumors with elevated TIL levels (p = 0.001). The ADC values and the enhancing characteristics were the most important factors in predicting TIL levels, according to logistic regression analysis, and when combined, they demonstrated the strongest ability to distinguish between the two groups (AUC = 0.744). Conclusions: MRI features, particularly ADC values and enhancement characteristics, may play a pivotal role in the assessment of TIL levels in BC before surgery. This could help patients to better customize treatments to the features of their tumors. Full article