Differentiation of low-grade intestinal T-cell lymphoma (LGITL) from lymphoplasmacytic enteritis (LPE) in cats is a diagnostic challenge for pathologists.
Characterize histologic, Bio Med Frontiers immunohistochemical, and molecular features of LGITL and LPE.
Forty-four client-owned cats, 22 diagnosed with LGITL and 22 with LPE.
Prospective, cohort study. Clinical suspicion of LGITL or LPE was based on persistent gastrointestinal signs, unresponsive to empirical treatments. All cats underwent a standardized diagnostic evaluation, including biopsy (preferentially full-thickness), and were diagnosed with LGITL or LPE after review of clinical, laboratory, sonographic, histologic, immunohistochemical, and clonality results.
A monomorphic lymphocytic population (22/22, 100%) and in-depth mucosal infiltration (15/22, 68%) were hallmarks of LGITL.
Epithelial patterns (nests and plaques) were significantly more frequent in LGITL (11/22, 50%) than in LPE (1/22, 5%) cases (P = .001). A CD3+ lymphocytic apical-to-basal gradient was observed in 9/22 (41%) of LGITL vs 1/22 (5%) of LPE cases (P = .004). Most LPE cases (17/18, 94%) featured marked fibrosis in the superficial part of the lamina propria. The Ki-67 20%- and 30%-thresholds discriminated between LGITL and LPE within both the epithelium (specificity >95%) and lamina propria (specificity >95%), respectively.
All LGITL cases were CD3+ pSTAT3- and pSTAT5+. T-cell receptor gamma chain gene rearrangements indicated monoclonality in 86% of LGITL cases. Surprisingly, 70% of LPE cases featured monoclonality (40%) or monoclonality on a polyclonal background (30%).
We identified new histologic, immunohistochemical, and clonality criteria to distinguish LGITL from LPE.
CD20; CD3; JAK-STAT; Ki-67; PARR; alimentary lymphoma; clonality; epithelium; fibrosis; full-thickness intestinal biopsies; gradient; histology; immunohistochemistry; inflammatory bowel disease; lamina propria; monoclonal; nest; plaque; polyclonal.
PAX8 lineage-driven T cell engaging antibody for the treatment of high-grade serous ovarian cancer.
High-grade serous ovarian cancers (HGSOC) represent the most common subtype of ovarian malignancies. Due to Learn More the frequency of late-stage diagnosis and high rates of recurrence following standard of care treatments, novel therapies are needed to promote durable responses.
We investigated the anti-tumor activity of CD3 T cell engaging bispecific antibodies (TCBs) directed against the PAX8 lineage-driven HGSOC tumor antigen LYPD1 and demonstrated that anti-LYPD1 TCBs induce T cell activation and promote in vivo tumor growth inhibition in LYPD1-expressing HGSOC.
To selectively target LYPD1-expressing tumor cells with high expression while sparing cells with low expression, we coupled bivalent low-affinity anti-LYPD1 antigen-binding fragments (Fabs) with the anti-CD3 scFv.
In contrast to the monovalent anti-LYPD1 high-affinity TCB (VHP354), the bivalent low-affinity anti-LYPD1 TCB (QZC131) demonstrated antigen density-dependent selectivity and showed tolerability in cynomolgus monkeys at the maximum dose tested of 3 mg/kg.
Collectively, these data demonstrate that bivalent TCBs directed against LYPD1 have compelling efficacy and safety profiles to support its use as a treatment for high-grade serous ovarian cancers.
High Fat Diet-Induced CD8 + T Cells in Adipose Tissue Mediate Macrophages to Sustain Low-Grade Chronic Inflammation.
Obesity in the United States and worldwide reached epidemic proportions within the last 20 years. Obesity is a very powerful health determinant or indicator that facilitates the development and progression of several metabolic diseases, insulin resistance, and low-grade chronic inflammation.
Low-grade chronic inflammation in adipose tissue (AT) is marked by the accumulation of T cells, macrophages, and other immune cells and increased production of proinflammatory cytokines.
During the onset of obesity but before the influx of macrophages, the AT is infiltrated by T cells that are strongly implicated in the initiation of obesity-associated inflammation.
In comparing mice fed a high-fat diet (HFD) with those fed a normal diet (ND), we observed in HFD epididymal AT induction and infiltration of activated T cells, an accumulation and polarization of macrophages, and an increase in populations of activated CD4+ T cells and CD8+ T cells that express CXCR3 or killer cell lectin-like receptor subfamily G member 1 (KLRG1).
Levels of inflammatory cytokines and leptin and the results of in vitro co-culture experiments revealed interactions among HFD- and ND-induced CD8+ T cells, macrophages, and adipocytes.
Our findings suggest that obese tissues activate and induce both CD4+ and CD8+ CD69+ T cells and augment the expression of CXCR3 receptors, which promotes the recruitment and numbers of pro-inflammatory M1 macrophages to maintain low-grade chronic inflammation.
The results support the hypothesis that CXCR3-expressing CD8+T cells play an essential role in the initiation and maintenance of adipose tissue inflammation.
Prognostic image-based quantification of CD8CD103 T cell subsets in high-grade serous ovarian cancer patients
CD103-positive tissue resident memory-like CD8+ T cells (CD8CD103 TRM) are associated with improved prognosis across malignancies, including high-grade serous ovarian cancer (HGSOC).
However, whether quantification of CD8, CD103 or both is required to improve existing survival prediction and whether all HGSOC patients or only specific subgroups of patients benefit from infiltration, remains unclear.
To address this question, we applied image-based quantification of CD8 and CD103 multiplex immunohistochemistry in the intratumoral and stromal compartments of 268 advanced-stage HGSOC patients from two independent clinical institutions.
Infiltration of CD8CD103 immune cell subsets was independent of clinicopathological factors.
Our results suggest CD8CD103 TRM quantification as a superior method for prognostication compared to single CD8 or CD103 quantification. A survival benefit of CD8CD103 TRM was observed only in patients treated with primary cytoreductive surgery.
Moreover, survival benefit in this group was limited to patients with no macroscopic tumor lesions after surgery. This approach provides novel insights into the prognostic stratification of HGSOC patients and may contribute to personalized treatment strategies in the future.
Spatial cytotoxic and memory T cells in tumors predict superior survival outcomes in patients with high-grade serous ovarian cancer.
Although the association between tumor-infiltrating CD3+ T and CD8+ T cells and superior survival in high-grade serous ovarian cancer (HGSOC) has been observed, the different spatial localization of tumor-infiltrating lymphocytes (TILs) possesses heterogeneous effects.
We performed localized measurements in 260 HGSOC from 2 independent cohorts represented in tissue microarray format to determine the localized expression pattern and clinical significance of CD3+ T, CD8+ T, and CD45RO+ cells in HGSOC.
Different density of spatial localization of CD3+ T, CD8+ T, and CD45RO+ cells exhibited heterogeneous association with OS. The combination of the center of the tumor and invasive margin localized CD8+ T cells (CD8CT&IM ) with the same margin localized CD45RO (CD45ROCT&IM ) was the most robust prognostic predictor.
Immune score (IS) was constructed by integrating FIGO stage with CD8CT&IM and CD45ROIM&CT and had the best prognostic value in HGSOC. The low-, intermediate-, and high-IS groups were observed in 44.7%, 41.6%, and 13.7% of patients, respectively.
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Low-IS identified patients were at higher risk of death compared to high-IS identified patients (HR = 12.426; 95% CI 5.317-29.039, p < 0.001); meanwhile, we evaluate the RMSTs over 10 years of follow-up and obtained RMST values of 104.09 months (95% CI 96.31-111.87 months) in the high-IS group, 75.26 months (95% CI 59.92-90.60 months) in the intermediate-IS group, and 48.68 months (95%CI 38.82-58.54 months) in the low-IS group. In general, spatial localization can modulate the clinical effects of TILs in HGSOC. Thus, the spatial expression of CD8 and CD45RO could aid clinicians to determine the follow-up plan of patients with HGSOC.
