scholarly journals DNA Methylation based glioblastoma subclassification is related to tumoral T cell infiltration and patient survival

2020 ◽  
Author(s):  
Joost Dejaegher ◽  
Lien Solie ◽  
Zoé Hunin ◽  
Raf Sciot ◽  
David Capper ◽  
...  
Keyword(s):  
Dna Methylation ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Methylation Pattern ◽  
Response To Therapy ◽  
Cell Infiltration ◽  
Mesenchymal Tumors ◽  
T Cell Infiltration

Abstract Background Histologically classified Glioblastomas (GBM) can have different clinical behavior and response to therapy, for which molecular subclassifications have been proposed. We evaluated the relationship of epigenetic GBM subgroups with immune cell infiltrations, systemic immune changes during radiochemotherapy and clinical outcome. Methods 450K genome-wide DNA methylation was assessed on tumor tissue from 93 patients with newly diagnosed GBM, treated with standard radiochemotherapy and experimental immunotherapy. Tumor infiltration of T cells, myeloid cells and PD-1 expression were evaluated. Circulating immune cell populations and selected cytokines were assessed on blood samples taken before and after radiochemotherapy. Results Forty-two tumors had a mesenchymal, 27 a RTK II, 17 a RTK I and 7 an IDH DNA methylation pattern Mesenchymal tumors had the highest amount of tumor-infiltrating CD3+ and CD8+ T cells and IDH tumors the lowest. There were no significant differences for CD68+ cells, FoxP3+ cells and PD-1 expression between groups. Systemically, there was a relative increase of CD8+ T cells and CD8+ PD-1 expression and a relative decrease of CD4+ T cells after radiochemotherapy in all subgroups except IDH tumors. Overall survival was the longest in the IDH group (median 36 months), intermediate in RTK II tumors (27 months) and significantly lower in mesenchymal and RTK I groups (15.5 and 16 months respectively). Conclusions Methylation based stratification of GBM is related to T cell infiltration and survival, with IDH and mesenchymal tumors representing both ends of a spectrum. DNA methylation profiles could be useful in stratifying patients for immunotherapy trials.

Antitumor activity of concurrent blockade of immune checkpoint molecules CTLA-4 and PD-1 in preclinical models.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3061-3061 ◽  
Author(s):  
Mark Selby ◽  
John Engelhardt ◽  
Li-Sheng Lu ◽  
Michael Quigley ◽  
Changyu Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antitumor Activity ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Cell Infiltration ◽  
Preclinical Models ◽  
Concurrent Treatment ◽  
T Cell Infiltration ◽  
Synergistic Antitumor Activity

3061 Background: Interaction of immune checkpoint molecules PD-1 and CTLA-4 and their respective ligands attenuates antitumor T cell responses. In clinical studies, PD-1 blocking antibody (Ab) nivolumab (BMS-936558) or the CTLA-4 blocking Ab ipilimumab result in durable responses in multiple human malignancies. We describe the evaluation of concurrent treatment with anti-PD-1 and anti-CTLA-4 mAbs in preclinical models. Methods: Antitumor activity of treatment with murine homologs of anti-PD-1 (4H2-mIgG1) and anti-CTLA-4 (9D9-mIgG2b) was evaluated in MC38, a murine colon adenocarcinoma model. The effects of concurrent treatment on T cell infiltration of tumors, tumoral expression of PD-L1 and cytokine levels were explored. The preclinical safety profile of concurrent nivolumab + ipilimumab was assessed in a cynomolgus macaque model. Results: Concurrent treatment of MC38 tumors with 4H2-mIgG1 + 9D9-mIgG2b (10 mg/kg Q3d x 3) results in synergistic antitumor activity whereas efficacy with sequential dosing was similar to either agent alone. With concurrent treatment, dose reductions of one Ab relative to a fixed dose of the other resulted in retention of some antitumor activity. Anti-PD-1 enhanced CD8+ T cell infiltration of MC38 tumors and increased tumor PD-L1 expression. Anti-CTLA-4 treatment increased intratumoral CD8+ T cells and reduced intratumoral T regulatory cells. While concurrent treatment did not result in further increases in T cell infiltration, it increased expression of intratumoral cytokines. Anti-PD-1 resulted in down regulation of cell surface and intracellular levels of PD-1 in CD8+ T cells. In cynomolgus macaques, concurrent nivolumab + ipilimumab resulted in dose-dependent gastrointestinal toxicities (diarrhea; body weight loss) not observed in earlier cynomolgus studies with nivolumab and rarely with ipilimumab. These preclinical observations provided the rationale for a dose escalation trial (NCT01024231) of combined nivolumab + ipilimumab in advanced melanoma. Conclusions: Concurrent treatment with anti-PD-1/anti-CTLA-4 resulted in synergistic antitumor activity in preclinical models and supports the evaluation of the combination in clinical studies.

Immunogenomic classification of gastric cancer based on the tumor microenvironments expression of PD-L1 and CD8+ T-cell infiltration.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16578-e16578
Author(s):  
Yu Chen ◽  
Gang Chen ◽  
Jia-ni Xiong ◽  
Bin Lan ◽  
Xuan Gao ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
Type I ◽  
T Cell Infiltration ◽  
Genetic Features

e16578 Background: Previous data has shown that a positive response to immunotherapy usually relies on active interactions between tumor cells and immunomodulators inside the tumor microenvironment (TME). The aim of this study was to classify gastric cancer (GC) subsets based on the TME immune status according to the expression of PD-L1 and infiltration of CD8+ T cells. Methods: One hundred and eighty-six tumor tissue from gastric cancer patients with a curative D2 gastrectomy were examined for evaluating PD-L1 and CD8+ T cells status using histopathologic analysis. The molecular characteristics of 289 GC samples in TCGA network were further analyzed to distinguish the genetic features of four immune subtypes depending on the presence of PD-L1/CD8+T cell. Results: GC samples were categorized into four types, type I (CD8+/PD-L1+, 60.3%), II (CD8-/PD-L1-, 11.8%), III (CD8-/PD-L1+, 0%), and IV (CD8+/PD-L1-, 27.9%), basing on PD-L1/CD8 expression. The PD-L1 expressing level was geographically associated with the intensity of CD8+ T cell infiltration which was significantly associated with disease-free survival (DFS) and overall survival (OS) (p = 0.003 and p = 0.006). Distinct patterns of genetic profile were described in four types of GC from TCGA database. Type I and III which PD-L1 were overly expressed had comparatively higher MSI and TMB, with EBV mainly enriched in Type I, whereas CIN was more likely to occur in PD-L1 aberrant types II and IV. SNV analysis illustrated higher gene mutations in oncogenes (PIK3CA and ERBB2), and in DNA damage repair related pathway, such as PRKDC, ATM, and SWI/SNF complexes (e.g. ARID1A) in Type I. However, TP53 mutations tend to enrich in Type II and IV. Similar results were obtained by transcriptome analysis. Conclusions: The genetic features of four immune subtypes proof that PD-L1 and CD8+ T cells status are reasonable immunogenomic classification of gastric cancer. SNV analysis prompts a potential mechanism for effectiveness of immunotherapy in Type I patients. Overall, the results may be useful for the development of clinical treatments for the blockade of immune checkpoints.

PAX5 haploinsufficiency induces low T cell infiltration in the cancer microenvironment via reduced chemokines

2021 ◽  
Vol 21 ◽  
Author(s):  
Lei Wang ◽  
Xue Liang ◽  
Mi Liang ◽  
Dang Li ◽  
Jia Gu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Gene Editing ◽  
Immune Escape ◽  
Cell Infiltration ◽  
Loss Of Function ◽  
Wild Type ◽  
T Cell Infiltration ◽  
Wild Type Control

Aims: To investigate the effects of PAXT mutations on tumor immunity. Background: Loss of function of PAX5 plays a key role in PAX5 mutation tumor. Objective: PAX5 haploinsufficiency promoting tumorigenesis is related to immune escape, but there was no report about mechanisms of PAX5 mutation inducing tumor immunological escape. Method: We constructed the PAX5 haplodeletion A20 cell lines using gene-editing technology, built allografted A20 tumor models and evaluated the effect of PAX5 haplodeletion on T cells and chemokines in the tumor microenvironment (TME). Result: Our results from different methods indicated percentages of CD3+ CD4+ T cells and CD3+ CD8+ T cells in TME of PAX5 haplodeletion clones decreased significantly compared with that of PAX5 wild type control. Several chemokines, such as Ccl2, Ccl4, Cxcl9 and Cxcl10, in TME of PAX5. Conclusion: Our study showed that PAX5 haploinsufficiency induced low T cell infiltration in TME using decreased chemokines.

Tumor-derived GDF-15 to suppress t-lymphocyte recruitment to the tumor microenvironment resulting in resistance to ANTI-PD-1 treatment.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14532-e14532
Author(s):  
Joerg Wischhusen ◽  
Markus Haake ◽  
Neha Vashist ◽  
Sabrina Genßler ◽  
Kilian Wistuba-Hamprecht ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cell ◽  
Serum Levels ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
T Cell Infiltration ◽  
Melanoma Patients

e14532 Background: Growth and differentiation factor 15 (GDF-15) is a divergent member of the TGF-β superfamily with low to absent expression in healthy tissue. GDF-15 has been linked to feto-maternal immune tolerance, to prevention of excessive immune cell infiltration during tissue damage, and to anorexia. Various major tumor types secrete high levels of GDF-15. In cancer patients, elevated GDF-15 serum levels correlate with poor prognosis and reduced overall survival (OS). Methods: Impact of a proprietary GDF-15 neutralizing antibody (CTL-002) regarding T cell trafficking was analyzed by whole blood adhesion assays, a HV18-MK melanoma-bearing humanized mouse model and a GDF-15-transgenic MC38 model. Additionally, patient GDF-15 serum levels were correlated with clinical response and overall survival in oropharyngeal squamous cell carcinoma (OPSCC) and melanoma brain metastases. Results: In whole blood cell adhesion assays GDF-15 impairs adhesion of T and NK cells to activated endothelial cells. Neutralization of GDF-15 by CTL-002 rescued T cell adhesion. In HV18-MK-bearing humanized mice CTL-002 induced a strong increase in TIL numbers. Subset analysis revealed an overproportional enrichment of T cells, in particular CD8+ T cells. As immune cell exclusion is detrimental for checkpoint inhibitor (CPI) therapy, a GDF-15-transgenic MC38 model was tested for anti-PD-1 therapy efficacy. In GDF-15 overexpressing MC38 tumors response to anti PD-1 therapy was reduced by 90% compared to wtMC38 tumors. Combining aPD-1 with CTL-002 resulted in 50% of the mice rejecting their GDF-15 overexpressing tumors. Clinically, inverse correlations of GDF-15 levels with CD8+ T cell infiltration were shown for HPV+ OPSCC and for melanoma brain metastases. GDF-15 serum levels were significantly higher in HPV- than in HPV+ OPSCC patient (p < 0.0001). Low GDF-15 levels corresponded to longer OS in both HPV- and HPV+ OPSCC. In two independent melanoma patient cohorts treated with nivolumab or pembrolizumab low baseline serum GDF-15 levels were predictive for clinical response to anti-PD1 treatment and superior OS. Bivariate analysis including LDH indicates that GDF-15 independently predicts poor survival in aPD-1 treated melanoma patients. Conclusions: Taken together our in vitro and in vivo data show that elevated GDF-15 levels block T-cell infiltration into tumor tissues. Neutralizing GDF-15 with CTL-002 restores the ability of T cells to extravasate blood vessels and enter tumor tissue both in vitro and in vivo. In melanoma, patients with higher GDF-15 levels have significantly shorter survival and are less likely to respond to anti-PD1 therapy. GDF-15 may thus serve as a new predictive biomarker for anti-PD1 response, but most importantly also represents a novel target for cancer immunotherapy to improve tumor immune cell infiltration and response to anti-PD1 therapy.

scholarly journals Multi-Parameter Quantitative Imaging of Tumor Microenvironments Reveals Perivascular Immune Niches Associated With Anti-Tumor Immunity

2021 ◽  
Vol 12 ◽  
Author(s):  
Caleb R. Stoltzfus ◽  
Ramya Sivakumar ◽  
Leo Kunz ◽  
Brandy E. Olin Pope ◽  
Elena Menietti ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Spatial Analysis ◽  
Blood Vessels ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
Response To Therapy ◽  
Disease Outcome ◽  
Tumor Microenvironments

Tumors are populated by a multitude of immune cell types with varied phenotypic and functional properties, which can either promote or inhibit anti-tumor responses. Appropriate localization and function of these cells within tumors is critical for protective immunity, with CD8 T cell infiltration being a biomarker of disease outcome and therapeutic efficacy. Recent multiplexed imaging approaches have revealed highly complex patterns of localization for these immune cell subsets and the generation of distinct tumor microenvironments (TMEs), which can vary among cancer types, individuals, and within individual tumors. While it is recognized that TMEs play a pivotal role in disease progression, a better understanding of their composition, organization, and heterogeneity, as well as how distinct TMEs are reshaped with immunotherapy, is necessary. Here, we performed spatial analysis using multi-parameter confocal imaging, histocytometry, and CytoMAP to study the microanatomical organization of immune cells in two widely used preclinical cancer models, the MC38 colorectal and KPC pancreatic murine tumors engineered to express human carcinoembryonic antigen (CEA). Immune responses were examined in either unperturbed tumors or after immunotherapy with a CEA T cell bispecific (CEA-TCB) surrogate antibody and anti-PD-L1 treatment. CEA-TCB mono and combination immunotherapy markedly enhanced intra-tumoral cellularity of CD8 T cells, dominantly driven by the expansion of TCF1-PD1+ effector T cells and with more minor increases in TCF1+PD1+ resource CD8 T cells. The majority of infiltrating T cells, particularly resource CD8 T cells, were colocalized with dendritic cells (DCs) or activated MHCII+ macrophages, but largely avoided the deeper tumor nest regions composed of cancer cells and non-activated macrophages. These myeloid cell – T cell aggregates were found in close proximity to tumor blood vessels, generating perivascular immune niches. This perivascular TME was present in untreated samples and markedly increased after CEA-TCB therapy, with its relative abundance positively associated with response to therapy. Together, these studies demonstrate the utility of advanced spatial analysis in cancer research by revealing that blood vessels are key organizational hubs of innate and adaptive immune cells within tumors, and suggesting the likely relevance of the perivascular immune TME in disease outcome.

scholarly journals Identification of Key Genes Related to CD8+ T-Cell Infiltration as Prognostic Biomarkers for Lung Adenocarcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Minjun Du ◽  
Yicheng Liang ◽  
Zixu Liu ◽  
Xingkai Li ◽  
Mei Liang ◽  
...  
Keyword(s):  
Risk Assessment ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Assessment Model ◽  
Cell Infiltration ◽  
Risk Assessment Model ◽  
T Cell Infiltration ◽  
Key Genes

BackgroundCD8+ T cells are one of the central effector cells in the immune microenvironment. CD8+ T cells play a vital role in the development and progression of lung adenocarcinoma (LUAD). This study aimed to explore the key genes related to CD8+ T-cell infiltration in LUAD and to develop a novel prognosis model based on these genes.MethodsWith the use of the LUAD dataset from The Cancer Genome Atlas (TCGA), the differentially expressed genes (DEGs) were analyzed, and a co-expression network was constructed by weighted gene co-expression network analysis (WGCNA). Combined with the CIBERSORT algorithm, the gene module in WGCNA, which was the most significantly correlated with CD8+ T cells, was selected for the subsequent analyses. Key genes were then identified by co-expression network analysis, protein–protein interactions network analysis, and least absolute shrinkage and selection operator (Lasso)-penalized Cox regression analysis. A risk assessment model was built based on these key genes and then validated by the dataset from the Gene Expression Omnibus (GEO) database and multiple fluorescence in situ hybridization experiments of a tissue microarray.ResultsFive key genes (MZT2A, ALG3, ATIC, GPI, and GAPDH) related to prognosis and CD8+ T-cell infiltration were identified, and a risk assessment model was established based on them. We found that the risk score could well predict the prognosis of LUAD, and the risk score was negatively related to CD8+ T-cell infiltration and correlated with the advanced tumor stage. The results of the GEO database and tissue microarray were consistent with those of TCGA. Furthermore, the risk score was higher significantly in tumor tissues than in adjacent lung tissues and was correlated with the advanced tumor stage.ConclusionsThis study may provide a novel risk assessment model for prognosis prediction and a new perspective to explore the mechanism of tumor immune microenvironment related to CD8+ T-cell infiltration in LUAD.

scholarly journals The anti-tumor effects of cetuximab in combination with VTX-2337 are T cell dependent

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yinwen Cheng ◽  
Nicholas Borcherding ◽  
Ayomide Ogunsakin ◽  
Caitlin D. Lemke-Miltner ◽  
Katherine N. Gibson-Corley ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Mouse Models ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Syngeneic Mouse ◽  
T Cell Infiltration ◽  
Cancer Immunotherapeutic

AbstractThe Toll-like receptor 8 (TLR8) agonist VTX-2337 (motolimod) is an anti-cancer immunotherapeutic agent that is believed to augment natural killer (NK) and dendritic cell (DC) activity. The goal of this work is to examine the role of TLR8 expression/activity in head and neck squamous cell carcinoma (HNSCC) to facilitate the prediction of responders to VTX-2337-based therapy. The prognostic role of TLR8 expression in HNSCC patients was assessed by TCGA and tissue microarray analyses. The anti-tumor effect of VTX-2337 was determined in SCCVII/C3H, mEERL/C57Bl/6 and TUBO-human EGFR/BALB/c syngeneic mouse models. The effect of combined VTX-2337 and cetuximab treatment on tumor growth, survival and immune cell recruitment was assessed. TLR8 expression was associated with CD8+ T cell infiltration and favorable survival outcomes. VTX-2337 delayed tumor growth in all 3 syngeneic mouse models and significantly increased the survival of cetuximab-treated mice. The anti-tumor effects of VTX-2337+ cetuximab were accompanied by increased splenic lymphoid DCs and IFNγ+ CD4+ and tumor-specific CD8+ T cells. Depletion of CD4+ T cells, CD8+ T cells and NK cells were all able to abolish the anti-tumor effect of VTX-2337+ cetuximab. Altogether, VTX-2337 remains promising as an adjuvant for cetuximab-based therapy however patients with high TLR8 expression may be more likely to derive benefit from this drug combination compared to patients with low TLR8 expression.

scholarly journals Direct CD137 costimulation of CD8 T cells promotes retention and innate-like function within nascent atherogenic foci

2019 ◽  
Vol 316 (6) ◽  
pp. H1480-H1494 ◽  
Author(s):  
Maria M. Xu ◽  
Antoine Ménoret ◽  
Sarah-Anne E. Nicholas ◽  
Sebastian Günther ◽  
Eric J. Sundberg ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Antigen Recognition ◽  
Cell Infiltration ◽  
Antigen Specificity ◽  
Effector Cells ◽  
T Cell Infiltration

Effector CD8 T cells infiltrate atherosclerotic lesions and are correlated with cardiovascular events, but the mechanisms regulating their recruitment and retention are not well understood. CD137 (4–1BB) is a costimulatory receptor induced on immune cells and expressed at sites of human atherosclerotic plaque. Genetic variants associated with decreased CD137 expression correlate with carotid-intimal thickness and its deficiency in animal models attenuates atherosclerosis. These effects have been attributed in part to endothelial responses to low and disturbed flow (LDF), but CD137 also generates robust effector CD8 T cells as a costimulatory signal. Thus, we asked whether CD8 T cell-specific CD137 stimulation contributes to their infiltration, retention, and IFNγ production in early atherogenesis. We tested this through adoptive transfer of CD8 T cells into recipient C57BL/6J mice that were then antigen primed and CD137 costimulated. We analyzed atherogenic LDF vessels in normolipidemic and PCSK9-mediated hyperlipidemic models and utilized a digestion protocol that allowed for lesional T-cell characterization via flow cytometry and in vitro stimulation. We found that CD137 activation, specifically of effector CD8 T cells, triggers their intimal infiltration into LDF vessels and promotes a persistent innate-like proinflammatory program. Residence of CD137+ effector CD8 T cells further promoted infiltration of endogenous CD8 T cells with IFNγ-producing potential, whereas CD137-deficient CD8 T cells exhibited impaired vessel infiltration, minimal IFNγ production, and reduced infiltration of endogenous CD8 T cells. Our studies thus provide novel insight into how CD137 costimulation of effector T cells, independent of plaque-antigen recognition, instigates their retention and promotes innate-like responses from immune infiltrates within atherogenic foci. NEW & NOTEWORTHY Our studies identify CD137 costimulation as a stimulus for effector CD8 T-cell infiltration and persistence within atherogenic foci, regardless of atherosclerotic-antigen recognition. These costimulated effector cells, which are generated in pathological states such as viral infection and autoimmunity, have innate-like proinflammatory programs in circulation and within the atherosclerotic microenvironment, providing mechanistic context for clinical correlations of cardiovascular morbidity with increased CD8 T-cell infiltration and markers of activation in the absence of established antigen specificity. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/effector-cd8-t-cells-seed-atherogenic-foci/ .

scholarly journals Tumoral HLA Class I and APM Expression and Its Effect on Intratumoral T-cell Reaction and Outcome in HPV-Negative Oral Squamous Cell Carcinoma

2020 ◽  
Author(s):  
Claudia Wickenhauser ◽  
Daniel Bethmann ◽  
Matthias Kappler ◽  
Alexander Walter Eckert ◽  
André Steven ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
T Cells ◽  
T Cell ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Hla Class I ◽  
T Cell Infiltration

Progression of oral squamous cell carcinoma (OSCC) has been associated with an escape of tumor cells from the host immune surveillance with growing evidence of its underlying molecular mechanisms and its interaction with the immune cell control. In this study the expression of HLA class I (HLA-I) antigens and of components of the antigen processing machinery (APM) was analyzed in 160 consecutive human papilloma virus (HPV)-negative OSCC lesions and correlated to tumor specific parameters, the intratumoral immune cell response and to the patients outcome. A heterogeneous, but predominantly lower constitutive protein expression of HLA-I APM components was seen in OSCC sections when compared to non-neoplastic cells. Based on the expression levels of HLA-I APM components three main OSCC subgroups were detected and categorized into HLA-Ihigh/APMhigh, HLA-Ilow/APMlow and HLA-Idiscordant high/low/APMhigh phenotypes. In the HLA-Ihigh/APMhigh group, the highest frequency of intratumoral CD8+ T cells and lowest number of CD8+ T cells close to FoxP3 cells was found. Despite being associated with the highest T cell infiltration, patients within this group presented the most unfavorable survival, which was most evident in stage T2 tumors. Thus, the presented findings strongly indicate the presence of additional factors involved in the immunomodulatory process of HPV-negative OSCC with a possible tumor-burden-dependent complex network of immune escape mechanisms beyond HLA-I/APM components and T cell infiltration in this tumor entity.

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