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Cancer Immunology, Immunotherapy : CII Jul 2024Tissue-resident memory CD103+CD8+ T cells (CD103+CD8+ TRMs) are important components of anti-tumor immunity. However, the significance of CD103+CD8+ TRMs in colorectal...
BACKGROUND
Tissue-resident memory CD103+CD8+ T cells (CD103+CD8+ TRMs) are important components of anti-tumor immunity. However, the significance of CD103+CD8+ TRMs in colorectal cancer (CRC) and their advantages remain unclear.
METHODS
Clinical data and specimens were used to evaluate the significance of CD103+CD8+ TRMs in CRC. A mouse subcutaneous tumorigenesis model and colony-formation assay were conducted to evaluate the anti-tumor effects of CD103+CD8+ TRMs. Finally, the infiltration density and function of CD103+CD8+ TRMs in the tumors were evaluated using flow cytometry.
RESULTS
In this study, we showed that highly infiltrated CD103+CD8+ TRMs were associated with earlier clinical stage and negative VEGF expression in CRC patients and predicted a favorable prognosis for CRC/CRC liver metastases patients. Interestingly, we also found that CD103+CD8+ TRMs may have predictive potential for whether CRC develops liver metastasis in CRC. In addition, we found a positive correlation between the ratio of the number of α-SMA+ vessels to the sum of the number of α-SMA+ and CD31+ vessels in CRC, and the infiltration level of CD103+CD8+ TRMs. In addition, anti-angiogenic therapy promoted infiltration of CD103+CD8+ TRMs and enhanced their ability to secrete interferon (IFN)-γ, thus further improving the anti-tumor effect. Moreover, in vivo experiments showed that compared with peripheral blood CD8+ T cells, CD103+CD8+ TRMs infused back into the body could also further promote CD8+ T cells to infiltrate the tumor, and they had a stronger ability to secrete IFN-γ, which resulted in better anti-tumor effects.
CONCLUSION
We demonstrated that CD103+CD8+ TRMs have the potential for clinical applications and provide new ideas for combined anti-tumor therapeutic strategies, such as anti-tumor angiogenesis therapy and CAR-T combined immunotherapy.
Topics: Colorectal Neoplasms; Integrin alpha Chains; Animals; Humans; CD8-Positive T-Lymphocytes; Mice; Liver Neoplasms; Antigens, CD; Prognosis; Female; Male; Immunologic Memory; Biomarkers, Tumor; Memory T Cells; Lymphocytes, Tumor-Infiltrating; Middle Aged
PubMed: 38954030
DOI: 10.1007/s00262-024-03709-2 -
Supportive Care in Cancer : Official... Jul 2024Continuous lenalidomide maintenance treatment after autologous stem cell transplantation delivers improvement in progression free and overall survival among newly...
PURPOSE
Continuous lenalidomide maintenance treatment after autologous stem cell transplantation delivers improvement in progression free and overall survival among newly diagnosed multiple myeloma patients and has been the standard of care in the UK since March 2021. However, there is scant information about its impact on patients' day-to-day lives. This service evaluation aimed to qualitatively assess patients receiving lenalidomide treatment at a cancer centre in London, in order that the service might better align with needs and expectations of patients.
METHODS
We conducted 20 semi-structured interviews among myeloma patients who were on continuous lenalidomide maintenance treatment at a specialist cancer centre in London. Members of the clinical team identified potentially eligible participants to take part, and convenience sampling was used to select 10 male and 10 female patients, median age of 58 (range, 45-71). The median treatment duration was 11 months (range, 1-60 months). Participants were qualitatively interviewed following the same semi-structured interview guide, which was designed to explore patient experience and insights of lenalidomide. Reflexive thematic analysis was used for data analysis.
RESULTS
Four overarching themes were as follows: (i) lenalidomide: understanding its role and rationale; (ii) reframing the loss of a treatment-free period to a return to normal life; (iii) the reality of being on lenalidomide: balancing hopes with hurdles; (iv) gratitude and grievances: exploring mixed perceptions of care and communication. Results will be used to enhance clinical services by tailoring communication to better meet patients' preferences when making treatment decisions.
CONCLUSION
This study highlights that most patients feel gratitude for being offered continuous lenalidomide and perceive it as alleviating some fears concerning relapse. It reveals variations in side effects in different age groups; younger patients reported no/negligible side effects, whilst several older patients with comorbidities described significant symptom burden, occasionally leading to treatment discontinuation which caused distress at the perceived loss of prolonged remission. Future research should prioritise understanding the unique needs of younger patients living with multiple myeloma.
Topics: Humans; Multiple Myeloma; Lenalidomide; Male; Female; Middle Aged; Aged; Qualitative Research; London; Maintenance Chemotherapy; Interviews as Topic; Quality of Life; Transplantation, Autologous; Antineoplastic Agents
PubMed: 38954025
DOI: 10.1007/s00520-024-08663-4 -
Cancer Immunology, Immunotherapy : CII Jul 2024Insofar as they play an important role in the pathogenesis of colorectal cancer (CRC), this study analyzes the serum profile of cytokines, chemokines, growth factors,...
Insofar as they play an important role in the pathogenesis of colorectal cancer (CRC), this study analyzes the serum profile of cytokines, chemokines, growth factors, and soluble receptors in patients with CRC and cancer-free controls as possible CRC signatures. Serum levels of 65 analytes were measured in patients with CRC and age- and sex-matched cancer-free controls using the ProcartaPlex Human Immune Monitoring 65-Plex Panel. Of the 65 tested analytes, 8 cytokines (CSF-3, IFN-γ, IL-12p70, IL-18, IL-20, MIF, TNF-α and TSLP), 8 chemokines (fractalkine, MIP-1β, BLC, Eotaxin-1, Eotaxin-2, IP-10, MIP-1a, MIP-3a), 2 growth factors (FGF-2, MMP-1), and 4 soluble receptors (APRIL, CD30, TNFRII, and TWEAK), were differentially expressed in CRC. ROC analysis confirmed the high association of TNF-α, BLC, Eotaxin-1, APRIL, and Tweak with AUC > 0.70, suggesting theranostic application. The expression of IFN-γ, IL-18, MIF, BLC, Eotaxin-1, Eotaxin-2, IP-10, and MMP1 was lower in metastatic compared to non-metastatic CRC; only AUC of MIF and MIP-1β were > 0.7. Moreover, MDC, IL-7, MIF, IL-21, and TNF-α are positively associated with tolerance to CRC chemotherapy (CT) (AUC > 0.7), whereas IL-31, Fractalkine, Eotaxin-1, and Eotaxin-2 were positively associated with resistance to CT. TNF-α, BLC, Eotaxin-1, APRIL, and Tweak may be used as first-line early detection of CRC. The variable levels of MIF and MIP-1β between metastatic and non-metastatic cases assign prognostic nature to these factors in CRC progression. Regarding tolerance to CT, MDC, IL-7, MIF, IL-21, and TNF-α are key when down-regulated or resistant to treatment is observed.
Topics: Humans; Colorectal Neoplasms; Female; Male; Cytokines; Middle Aged; Aged; Intercellular Signaling Peptides and Proteins; Chemokines; Treatment Outcome; Biomarkers, Tumor; Adult; Prognosis; Case-Control Studies
PubMed: 38954024
DOI: 10.1007/s00262-024-03746-x -
Cancer Immunology, Immunotherapy : CII Jul 2024Oral squamous cell carcinoma (OSCC), while common and with a favorable prognosis in early stages, presents a marked reduction in survival rate upon metastasis to lymph...
INTRODUCTION
Oral squamous cell carcinoma (OSCC), while common and with a favorable prognosis in early stages, presents a marked reduction in survival rate upon metastasis to lymph nodes. Early detection of lymph node metastasis via biomarkers could enhance the therapeutic strategy for OSCC. Here, we explored dendritic cells (DCs) and cytotoxic T-cells in tumour-draining lymph nodes (TDLNs) as potential biomarkers.
METHOD
Dendritic cells and cytotoxic T-cells in 33 lymph nodes were analyzed with multi-parameter flow cytometry in TDLNs, regional non-TDLNs surgically excised from 12 OSCC patients, and compared to 9 lymph nodes from patients with benign conditions.
RESULTS
Our results displayed a higher proportion of conventional cDC1s with immunosuppressive features in TDLN. Further, high PD-L1 expression on cDC1 in TDLNs was associated with metastasis and/or recurrent disease risk. Also, elevated levels of memory CD8 T-cells and terminally exhausted PD-1TCF-1CD8 T-cells were observed in TDLNs and non-TDLNs compared to healthy lymph nodes.
CONCLUSIONS
We conclude that TDLNs contain cells that could trigger an anti-tumor adaptive response, as evidenced by activated cDC1s and progenitor-like TCF-1 T-cells. The detection of high PDL1 expression on cDC1s was indicative of TDLN metastasis and an adverse prognosis, proposing that PD-L1 on dendritic cells in TDLN could serve as a predictive biomarker of OSCC patients with a worse prognosis.
Topics: Humans; Dendritic Cells; Mouth Neoplasms; Prognosis; Female; Male; Lymph Nodes; B7-H1 Antigen; Middle Aged; Aged; Lymphatic Metastasis; Carcinoma, Squamous Cell; Biomarkers, Tumor; Adult
PubMed: 38954023
DOI: 10.1007/s00262-024-03754-x -
Cancer Immunology, Immunotherapy : CII Jul 2024T cell receptor-engineered T cells (TCR-Ts) therapy is promising for cancer immunotherapy. Most studies have focused on identifying tumor-specific T cell receptors...
T cell receptor-engineered T cells (TCR-Ts) therapy is promising for cancer immunotherapy. Most studies have focused on identifying tumor-specific T cell receptors (TCRs) through predicted tumor neoantigens. However, current algorithms for predicting tumor neoantigens are unreliable and many neoantigens are derived from non-coding regions. Thus, the technological platform for identifying tumor-specific TCRs using natural antigens expressed on tumor cells is urgently needed. In this study, tumor organoids-enriched tumor infiltrating lymphocytes (oeT) were obtained by repeatedly stimulation of autologous patient-derived organoids (PDO) in vitro. The oeT cells specifically responded to autologous tumor PDO by detecting CD137 expression and the secretion of IFN-γ using enzyme-linked immunospot assay. The measurement of oeT cell-mediated killing of three-dimensional organoids was conducted using a caspase3/7 flow cytometry assay kit. Subsequently, tumor-specific T cells were isolated based on CD137 expression and their TCRs were identified through single-cell RT-PCR analysis. The specificity cytotoxicity of TCRs were confirmed by transferring to primary peripheral blood T cells. The co-culture system proved highly effective in generating CD8 tumor-specific oeT cells. These oeT cells effectively induced IFN-γ secretion and exhibited specificity in killing autologous tumor organoids, while not eliciting a cytotoxic response against normal organoids. The analysis conducted by TCRs revealed a significant expansion of T cells within a specific subset of TCRs. Subsequently, the TCRs were cloned and transferred to peripheral blood T cells generation engineered TCR-Ts, which adequately recognized and killed tumor cell in a patient-specific manner. The co-culture system provided an approach to generate tumor-specific TCRs from tumor-infiltrating lymphocytes of patients with colorectal cancer, and tumor-specific TCRs can potentially be used for personalized TCR-T therapy.
Topics: Humans; Lymphocytes, Tumor-Infiltrating; Receptors, Antigen, T-Cell; Coculture Techniques; Organoids; Antigens, Neoplasm; Neoplasms
PubMed: 38954022
DOI: 10.1007/s00262-024-03749-8 -
Cancer Immunology, Immunotherapy : CII Jul 2024In advanced non-small cell lung cancer (NSCLC), immune checkpoint inhibitor (ICI) monotherapy is often preferred over intensive ICI treatment for frail patients and...
PURPOSE
In advanced non-small cell lung cancer (NSCLC), immune checkpoint inhibitor (ICI) monotherapy is often preferred over intensive ICI treatment for frail patients and those with poor performance status (PS). Among those with poor PS, the additional effect of frailty on treatment selection and mortality is unknown.
METHODS
Patients in the veterans affairs national precision oncology program from 1/2019-12/2021 who received first-line ICI for advanced NSCLC were followed until death or study end 6/2022. Association of an electronic frailty index with treatment selection was examined using logistic regression stratified by PS. We also examined overall survival (OS) on intensive treatment using Cox regression stratified by PS. Intensive treatment was defined as concurrent use of platinum-doublet chemotherapy and/or dual checkpoint blockade and non-intensive as ICI monotherapy.
RESULTS
Of 1547 patients receiving any ICI, 66.2% were frail, 33.8% had poor PS (≥ 2), and 25.8% were both. Frail patients received less intensive treatment than non-frail patients in both PS subgroups (Good PS: odds ratio [OR] 0.67, 95% confidence interval [CI] 0.51 - 0.88; Poor PS: OR 0.69, 95% CI 0.44 - 1.10). Among 731 patients receiving intensive treatment, frailty was associated with lower OS for those with good PS (hazard ratio [HR] 1.53, 95% CI 1.2 - 1.96), but no association was observed with poor PS (HR 1.03, 95% CI 0.67 - 1.58).
CONCLUSION
Frail patients with both good and poor PS received less intensive treatment. However, frailty has a limited effect on survival among those with poor PS. These findings suggest that PS, not frailty, drives survival on intensive treatment.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Male; Female; Aged; Immunotherapy; Immune Checkpoint Inhibitors; Middle Aged; Frailty; Aged, 80 and over
PubMed: 38954019
DOI: 10.1007/s00262-024-03763-w -
Cancer Immunology, Immunotherapy : CII Jul 2024Radiotherapy (RT) synergizes with immune checkpoint blockade (ICB). CD1c(BDCA-1)/CD141(BDCA-3) myeloid dendritic cells (myDC) in the tumor microenvironment are... (Randomized Controlled Trial)
Randomized Controlled Trial
A randomized phase II clinical trial of stereotactic body radiation therapy (SBRT) and systemic pembrolizumab with or without intratumoral avelumab/ipilimumab plus CD1c (BDCA-1)/CD141 (BDCA-3) myeloid dendritic cells in solid tumors.
BACKGROUND
Radiotherapy (RT) synergizes with immune checkpoint blockade (ICB). CD1c(BDCA-1)/CD141(BDCA-3) myeloid dendritic cells (myDC) in the tumor microenvironment are indispensable at initiating effector T-cell responses and response to ICB.
METHODS
In this phase II clinical trial, anti-PD-1 ICB pretreated oligometastatic patients (tumor agnostic) underwent a leukapheresis followed by isolation of CD1c(BDCA-1)/CD141(BDCA-3) myDC. Following hypofractionated stereotactic body RT (3 × 8 Gy), patients were randomized (3:1). Respectively, in arm A (immediate treatment), intratumoral (IT) ipilimumab (10 mg) and avelumab (40 mg) combined with intravenous (IV) pembrolizumab (200 mg) were administered followed by IT injection of myDC; subsequently, IV pembrolizumab and IT ipilimumab/avelumab were continued (q3W). In arm B (contemporary control arm), patients received IV pembrolizumab, with possibility to cross-over at progression. Primary endpoint was 1-year progression-free survival rate (PFS). Secondary endpoints were safety, feasibility, objective response rate, PFS, and overall survival (OS).
RESULTS
Thirteen patients (10 in arm A, eight non-small cell lung cancer, and five melanoma) were enrolled. Two patients crossed over. One-year PFS rate was 10% in arm A and 0% in arm B. Two patients in arm A obtained a partial response, and one patient obtained a stable disease as best response. In arm B, one patient obtained a SD. Median PFS and OS were 21.8 weeks (arm A) versus 24.9 (arm B), and 62.7 versus 57.9 weeks, respectively. An iatrogenic pneumothorax was the only grade 3 treatment-related adverse event.
CONCLUSION
SBRT and pembrolizumab with or without IT avelumab/ipilimumab and IT myDC in oligometastatic patients are safe and feasible with a clinically meaningful tumor response rate. However, the study failed to reach its primary endpoint.
TRIAL REGISTRATION NUMBER
Clinicaltrials.gov: NCT04571632 (09 AUG 2020).
EUDRACT
2019-003668-32. Date of registration: 17 DEC 2019, amendment 1: 6 MAR 2021, amendment 2: 4 FEB 2022.
Topics: Humans; Antibodies, Monoclonal, Humanized; Female; Male; Aged; Middle Aged; Radiosurgery; Dendritic Cells; Ipilimumab; Adult; Antineoplastic Combined Chemotherapy Protocols; Neoplasms; Thrombomodulin; Aged, 80 and over; Combined Modality Therapy; Myeloid Cells; Glycoproteins; Antigens, CD1
PubMed: 38954010
DOI: 10.1007/s00262-024-03751-0 -
Pediatric Surgery International Jul 2024This study aims to examine the clinical characteristics and surgical management of pediatric testicular epidermoid cysts, thereby contributing to the existing body of...
OBJECTIVE
This study aims to examine the clinical characteristics and surgical management of pediatric testicular epidermoid cysts, thereby contributing to the existing body of knowledge pertinent to the diagnosis and therapeutic intervention s for this condition.
METHODS
A retrospective analysis was conducted on the clinical records of 23 pediatric patients diagnosed with testicular epidermoid cysts, who were admitted to our institution between April 2013 and February 2024. Concurrently, a comprehensive review and analysis of pertinent literature were undertaken to augment the findings.
RESULTS
The mean age at which the onset of epidermoid cysts was observed was 6.0 years. All cases were singular and unilateral. B-ultrasound diagnosis categorized 6 cases as epidermoid cysts, 11 as teratomas, and 6 as indeterminate, yielding a diagnostic sensitivity of 26.1%. All patients underwent testicle-sparing mass resection, and nine patients underwent rapid intraoperative frozen section analysis, revealing eight cases of testicular epidermoid cysts and one teratoma, with a diagnostic sensitivity of 88.89%. Postoperative histopathological examination confirmed the diagnosis of testicular epidermoid cyst.
CONCLUSIONS
Pediatric testicular epidermoid cysts are an uncommon occurrence, primarily presenting as a painless scrotal mass, which can mimic the clinical features of malignant testicular tumors. Imaging modalities and histopathological assessment are pivotal in the diagnostic process for pediatric testicular epidermoid cysts. For cases where B-ultrasound is inconclusive, rapid intraoperative pathological examination should be considered.
Topics: Humans; Male; Epidermal Cyst; Retrospective Studies; Child; Child, Preschool; Testicular Diseases; Adolescent; Infant; Testis; Ultrasonography; Teratoma
PubMed: 38954009
DOI: 10.1007/s00383-024-05750-9 -
Cancer Immunology, Immunotherapy : CII Jul 2024Although nivolumab prolongs overall survival (OS) in pretreated patients with metastatic renal cell carcinoma (mRCC), underlining clinical and biological features of...
BACKGROUND
Although nivolumab prolongs overall survival (OS) in pretreated patients with metastatic renal cell carcinoma (mRCC), underlining clinical and biological features of long-term responses are still to be determined. This study aims to investigate clinical and pathological characteristics of mRCC patients who achieved long-term responses during nivolumab treatment.
MATERIALS AND METHODS
A retrospective analysis was performed on mRCC patients receiving nivolumab as second or further therapy line between May 2016 and January 2019 in 34 Italian Oncology Centres. Outcome assessments and logistic regression were performed to evaluate factors influencing long-term responses.
RESULTS
A total of 571 patients with a median age of 61 years (range 17-85) were included in the analysis. With a median follow-up of 22.1 (1.0-89.0) months, 23.1% of patients were 2-year progression-free on treatment with nivolumab, hence they were categorized as long-term responders. Baseline characteristics, including age, gender, and histology, were similar between long- and short-term responders. Karnofsky Performance Status ≥ 80% was significantly associated with long-term response (p = 0.02), while bone metastases (p = 0.03), International mRCC Database Consortium intermediate-poor risk (p < 0.01) and Neutrophil-to-Lymphocyte Ratio ≥ 3.2 (p = 0.02) were associate with short-term responses. Long-term responders exhibited a median progression-free survival of 55.0 months versus 4.0 months of the short-term responders. The median OS was not reached in long-term responders while it was 17.0 months for short*term responders.
CONCLUSION
This retrospective analysis sheds light on factors associated with long-term response to nivolumab in mRCC. Understanding these clinical features will be essential for selecting patients who may mostly benefit from immunotherapy.
Topics: Humans; Nivolumab; Carcinoma, Renal Cell; Female; Male; Middle Aged; Aged; Adult; Kidney Neoplasms; Retrospective Studies; Aged, 80 and over; Young Adult; Adolescent; Antineoplastic Agents, Immunological; Follow-Up Studies
PubMed: 38954006
DOI: 10.1007/s00262-024-03741-2 -
Cancer Immunology, Immunotherapy : CII Jul 2024Γδ T cell infiltration into tumours usually correlates with improved patient outcome, but both tumour-promoting and tumoricidal effects of γδ T cells have been...
Γδ T cell infiltration into tumours usually correlates with improved patient outcome, but both tumour-promoting and tumoricidal effects of γδ T cells have been documented. Human γδ T cells can be divided into functionally distinct subsets based on T cell receptor (TCR) Vδ usage. Still, the contribution of these different subsets to tumour immunity remains elusive. Here, we provide a detailed γδ T cell profiling in colon tumours, using mass and flow cytometry, mRNA quantification, and TCR sequencing. δ chain usage in both the macroscopically unaffected colon mucosa and tumours varied considerably between patients, with substantial fractions of Vδ1, Vδ2, and non-Vδ1 Vδ2 cells. Sequencing of the Vδ complementarity-determining region 3 showed that almost all non-Vδ1 Vδ2 cells used Vδ3 and that tumour-infiltrating γδ clonotypes were unique for every patient. Non-Vδ1Vδ2 cells from colon tumours expressed several activation markers but few NK cell receptors and exhaustion markers. In addition, mRNA analyses showed that non-Vδ1 Vδ2 cells expressed several genes for proteins with tumour-promoting functions, such as neutrophil-recruiting chemokines, Galectin 3, and transforming growth factor-beta induced. In summary, our results show a large variation in γδ T cell subsets between individual tumours, and that Vδ3 cells make up a substantial proportion of γδ T cells in colon tumours. We suggest that individual γδ T cell composition in colon tumours may contribute to the balance between favourable and adverse immune responses, and thereby also patient outcome.
Topics: Humans; Receptors, Antigen, T-Cell, gamma-delta; Colonic Neoplasms; Adenocarcinoma; Phenotype; Female; Male; T-Lymphocyte Subsets; Aged; Middle Aged; Lymphocytes, Tumor-Infiltrating
PubMed: 38953978
DOI: 10.1007/s00262-024-03758-7