HLA-mediated tumor escape mechanisms that may impair immunotherapy clinical outcomes via T-cell activation

Mitral stenosis (MS) is a consequence of rheumatic heart disease that leads to heart failure requiring mechanical intervention. Percutaneous mitral commissurotomy (PMC) is the treatment of choice for the intervention, and currently there are no soluble markers associated with hemodynamic improvement after PMC. This study aims to determine the changes in cytokine/chemokine plasma levels, as well as T cell activation after PMC, and to investigate their association with immediate hemodynamic improvement and clinical outcomes. Plasma samples from eighteen patients with well-defined MS who underwent PMC and 12 healthy controls were analyzed using BioPlex immunoassay. We observed that 16 out of the 27 (60%) molecules assessed were altered in patients' plasma pre-PMC as compared to control group. Of those, IL-1β, IL-12, IL-6, IL-4, PDGF, and CCL11 showed significant decrease after PMC. Stratifying the patients according to adverse outcome after a 28-month median follow up, we detected a significant reduction of IL-1β, IL-12, IL-6, IL-4, IFN-γ, CXCL-10, VEGF, FGF and PDGF post-PMC in patients without events, but not in those who presented adverse events during the follow-up. Patients with adverse outcomes had lower IL-10 pre-PMC, as compared to the ones without adverse events. In addition, the frequency of CD8+ activated memory cells was increased after PMC, while the frequency of CD4+ activated memory cells did not change. Our results show an association between the decrease of specific cytokines and changes in T cell activation with hemodynamic improvement post-PMC, as well as with long-term outcomes, suggesting their possible use as soluble markers for hemodynamic recovery after MS intervention.

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Optimization of T Cell Redirecting Strategies: Obtaining Inspirations From Natural Process of T Cell Activation

Frontiers in Immunology ◽

10.3389/fimmu.2021.664329 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yiyuan Gao ◽

Yuedi Wang ◽

Feifei Luo ◽

Yiwei Chu

Keyword(s):

T Cells ◽

T Cell ◽

Clinical Outcomes ◽

T Cell Activation ◽

Cell Activation ◽

Immunological Synapse ◽

Cell Receptor ◽

T Cell Response ◽

Antigen Receptors ◽

Cell Therapies

Chimeric antigen receptors (CARs) or bispecific antibodies (bsAbs) redirected T cell against tumors is one of the most promising immunotherapy approaches. However, insufficient clinical outcomes are still observed in treatments of both solid and non-solid tumors. Limited efficacy and poor persistence are two major challenges in redirected T cell therapies. The immunological synapse (IS) is a vital component during the T cell response, which largely determines the clinical outcomes of T cell-based therapies. Here, we review the structural and signaling characteristics of IS formed by natural T cells and redirected T cells. Furthermore, inspired by the elaborate natural T cell receptor-mediated IS, we provide potential strategies for higher efficacy and longer persistence of redirected T cells.

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Single-Cell Transcriptomic Analysis Reveals a Tumor-Reactive T Cell Signature Associated With Clinical Outcome and Immunotherapy Response In Melanoma

Frontiers in Immunology ◽

10.3389/fimmu.2021.758288 ◽

2021 ◽

Vol 12 ◽

Author(s):

Min Yan ◽

Jing Hu ◽

Yanyan Ping ◽

Liwen Xu ◽

Gaoming Liao ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Single Cell ◽

Clinical Outcomes ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cell Activation ◽

Cell Receptor ◽

Integrated Analysis ◽

Data Sets

The infiltration of tumor-reactive T cells in the tumor site is associated with better survival and immunotherapy response. However, tumor-reactive T cells were often represented by the infiltration of total CD8+ T cells, which was confounded by the presence of bystander T cells. To identify tumor-reactive T cells at the cancer lesion, we performed integration analyses of three scRNA-seq data sets of T cells in melanoma. Extensive heterogeneous functional states of T cells were revealed in the tumor microenvironment. Among these states, we identified a subset of tumor-reactive T cells which specifically expressed tumor-reactive markers and T cell activation signature, and were strongly enriched for larger T cell receptor (TCR) clones. We further identified and validated a tumor-reactive T cell signature (TRS) to evaluate the tumor reactivity of T cells in tumor patients. Patients with high TRS scores have strong immune activity and high mutation burden in the TCGA-SKCM cohort. We also demonstrated a significant association of the TRS with the clinical outcomes of melanoma patients, with higher TRS scores representing better survival, which was validated in four external independent cohorts. Furthermore, the TRS scores exhibited greater performance on prognosis prediction than infiltration levels of CD8+ T cells and previously published prognosis-related signatures. Finally, we observed the capability of TRS to predict immunotherapy response in melanoma. Together, based on integrated analysis of single-cell RNA-sequencing, we developed and validated a tumor-reactive-related signature that demonstrated significant association with clinical outcomes and response to immunotherapy.

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Correlation of mutational landscape and survival outcome of peripheral T-cell lymphomas

Experimental Hematology and Oncology ◽

10.1186/s40164-021-00200-x ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Yingying Ye ◽

Ning Ding ◽

Lan Mi ◽

Yunfei Shi ◽

Weiping Liu ◽

...

Keyword(s):

T Cell ◽

Clinical Outcomes ◽

T Cell Activation ◽

Cell Activation ◽

Cell Lymphoma ◽

Negative Impact ◽

Chromatin Modification ◽

Progression Free Survival ◽

Survival Outcome ◽

T Cell Lymphoma

Abstract Objective To explore the correlation of mutation landscape with clinical outcomes in patients with peripheral T-cell lymphoma (PTCL). Methods We retrospectively analyzed the clinicopathological and prognosis data of 53 patients with PTCL from November 2011 to December 2017. Targeted next-generation sequencing of a 659-gene panel was performed for tissues from 53 patients with PTCLs. The correlation of mutation landscape with clinical outcomes was analyzed. Results TET2 was the most frequently mutated gene (64%), followed by RHOA (43%), PCLO (23%), DNMT3A (19%), IDH2 (17%), PIEZO1 (17%) and TP53 (15%). When mutated genes were categorized into functional groups, the most common mutations were those involved in epigenetic/chromatin modification (75%), T-cell activation (74%), and the DNA repair/TP53 pathway (64%). TET2/TP53 mutations were significantly associated with positive B symptoms (P = 0.045), and elevated lactate dehydrogenase (LDH) level (P = 0.011). Moreover, TET2/TP53 mutation was a risk factor for PTCL patient survival (HR 3.574, 95% CI 1.069 − 11.941, P = 0.039). The occurrence of JAK/STAT pathway mutations in angioimmunoblastic T-cell lymphoma (AITL) patients conferred a worse progression-free survival (HR 2.366, 95% CI 0.9130–6.129, P = 0.0334). Conclusions Heterogeneous gene mutations occur in PTCL, some of which have a negative impact on the survival outcome.

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