Molecular subtyping of endometrial carcinoma cell lines uncovers subtype-specific targetable vulnerabilities.

Endometrial carcinoma (EC), the most common gynecologic cancer type in developed countries, encompasses four molecular subtypes (POLEmut, MMRd, p53abn, and NSMP) that have prognostic values and guide treatment decisions. Additionally, dual loss of ARID1A and ARID1B (referred to as ARID1A/B) characterizes a significant portion of dedifferentiated/undifferentiated EC (DD/UDEC), a rare but highly aggressive subtype of EC. To advance the translational research for ECs, we analyzed the genomic features of a panel of 39 EC cell lines, leading to the identification of cell lines representing each of these EC molecular subtype.

Tumor-Infiltrating Lymphocytes in Breast and Female Genital Tract Cancers: Overlooked Potential and Unexplored Frontiers.

Background: The growing success of cancer immunotherapies has led to significant advances in oncology. However, despite these promising developments, cancer-related mortality remains high for common cancer types such as breast and lower female genital tract cancers.

Method: Here, we synthesize recent findings on the prognostic relevance of tumor-infiltrating lymphocytes (TILs) in breast, endometrial, tubo-ovarian, and vulvar cancer.

Activated immune infiltrates expand opportunities for targeted therapy in p53-abnormal endometrial carcinoma.

Tumor protein p53 mutated/abnormal (p53abn) endometrial carcinomas account for over 50% of deaths but comprise only 15% of all endometrial carcinomas. Most patients show limited response to standard-of-care chemotherapy with or without radiotherapy, and only a minority of cases are amenable to targeted therapies like poly-ADP ribose polymerase (PARP) inhibitors and HER2-directed therapies. Recent immunotherapy clinical trials have demonstrated remarkable efficacy, not only in mismatch repair deficient (MMRd) tumors but also in a subset of mismatch repair-proficient (MMRp) tumors.

PRAME Immunohistochemistry for Distinguishing Vulvar and Vaginal Melanoma From Benign Melanocytic Nevi.

Vulvovaginal melanoma (VVM) is a rare but deadly disease, accounting for 5% of all vulvar malignancies, with a 5-yr survival rate of only 47% for all stages of the disease. VVM is a distinct subset of melanoma, with a unique genomic profile and underlying pathogenesis unassociated with sun exposure. Distinguishing these rare malignancies from very common pigmented lesions of the vulva and vagina is challenging as histologic features often overlap between entities.

Biomarkers for Immune Checkpoint Inhibitors in Renal Cell Carcinoma.

Immune checkpoint inhibitor (ICI) therapy has revolutionized renal cell carcinoma treatment. Patients previously thought to be palliative now occasionally achieve complete cures from ICI. However, since immunotherapies stimulate the immune system to induce anti-tumor immunity, they often lead to adverse autoimmunity.

Single-cell genomic variation induced by mutational processes in cancer.

How cell-to-cell copy number alterations that underpin genomic instability in human cancers drive genomic and phenotypic variation, and consequently the evolution of cancer, remains understudied. Here, by applying scaled single-cell whole-genome sequencing to wild-type, TP53-deficient and TP53-deficient;BRCA1-deficient or TP53-deficient;BRCA2-deficient mammary epithelial cells (13,818 genomes), and to primary triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSC) cells (22,057 genomes), we identify three distinct 'foreground' mutational patterns that are defined by cell-to-cell structural variation. Cell- and clone-specific high-level amplifications, parallel haplotype-specific copy number alterations and copy number segment length variation (serrate structural variations) had measurable phenotypic and evolutionary consequences.

Indicators Differentiating Thrombotic Thrombocytopenic Purpura From Other Thrombotic Microangiopathies in a Canadian Apheresis Referral Center.

Objectives: Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy (TMA) caused by ADAMTS13 deficiency with mortality of up to 90% in the absence of treatment, typically therapeutic plasma exchange (TPE). TTP presents similarly to other TMAs in which TPE is ineffective and associated with morbidity and additional costs. Thus, we sought to assess clinical and laboratory parameters differentiating TTP from other TMAs in our institution's catchment population.

Assessment of long non-coding RNA expression reveals novel mediators of the lung tumour immune response.

The tumour immune microenvironment is a crucial mediator of lung tumourigenesis, and characterizing the immune landscape of patient tumours may guide immunotherapy treatment regimens and uncover novel intervention points. We sought to identify the landscape of tumour-infiltrating immune cells in the context of long non-coding RNA (lncRNAs), known regulators of gene expression. We examined the lncRNA profiles of lung adenocarcinoma (LUAD) tumours by interrogating RNA sequencing data from microdissected and non-microdissected samples (BCCRC and TCGA).

Hyperspectral cell sociology reveals spatial tumor-immune cell interactions associated with lung cancer recurrence.

Background: The tumor microenvironment (TME) is a complex mixture of tumor epithelium, stroma and immune cells, and the immune component of the TME is highly prognostic for tumor progression and patient outcome. In lung cancer, anti-PD-1 therapy significantly improves patient survival through activation of T cell cytotoxicity against tumor cells. Direct contact between CD8+ T cells and target cells is necessary for CD8+ T cell activity, indicating that spatial organization of immune cells within the TME reflects a critical process in anti-tumor immunity.

Somatic mutation-associated T follicular helper cell elevation in lung adenocarcinoma.

T follicular helper cells (Tfh) play crucial roles in the development of humoral immunity. In the B cell-rich germinal center of lymphoid organs, they select for high-affinity B cells and aid in their maturation. While Tfh have known roles in B cell malignancies and have prognostic value in some epithelial cancers, their role in lung tumour initiation and development is unknown.

A library-based screening method identifies neoantigen-reactive T cells in peripheral blood prior to relapse of ovarian cancer.

Mutated cancer antigens, or neoantigens, represent compelling immunological targets and appear to underlie the success of several forms of immunotherapy. While there are anecdotal reports of neoantigen-specific T cells being present in the peripheral blood and/or tumors of cancer patients, effective adoptive cell therapy (ACT) against neoantigens will require reliable methods to isolate and expand rare, neoantigen-specific T cells from clinically available biospecimens, ideally prior to clinical relapse. Here, we addressed this need using "mini-lines", large libraries of parallel T cell cultures, each originating from only 2,000 T cells.

Mapping the human T cell repertoire to recurrent driver mutations in MYD88 and EZH2 in lymphoma.

Oncogenic "driver" mutations are theoretically attractive targets for the immunotherapy of lymphoid cancers, yet the proportion that can be recognized by T cells remains poorly defined. To address this issue without any confounding effects of the patient's immune system, we assessed T cells from 19 healthy donors for recognition of three common driver mutations in lymphoma: , and . Donors collectively expressed the 10 most prevalent HLA class I alleles, including HLA-A*02:01.

Low Mutation Burden in Ovarian Cancer May Limit the Utility of Neoantigen-Targeted Vaccines.

Due to advances in sequencing technology, somatically mutated cancer antigens, or neoantigens, are now readily identifiable and have become compelling targets for immunotherapy. In particular, neoantigen-targeted vaccines have shown promise in several pre-clinical and clinical studies. However, to date, neoantigen-targeted vaccine studies have involved tumors with exceptionally high mutation burdens.

Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival.

Somatic missense mutations can initiate tumorogenesis and, conversely, anti-tumor cytotoxic T cell (CTL) responses. Tumor genome analysis has revealed extreme heterogeneity among tumor missense mutation profiles, but their relevance to tumor immunology and patient outcomes has awaited comprehensive evaluation. Here, for 515 patients from six tumor sites, we used RNA-seq data from The Cancer Genome Atlas to identify mutations that are predicted to be immunogenic in that they yielded mutational epitopes presented by the MHC proteins encoded by each patient's autologous HLA-A alleles.

Surveillance of the tumor mutanome by T cells during progression from primary to recurrent ovarian cancer.

Purpose: Cancers accumulate mutations over time, each of which brings the potential for recognition by the immune system. We evaluated T-cell recognition of the tumor mutanome in patients with ovarian cancer undergoing standard treatment.

Experimental Design: Tumor-associated T cells from 3 patients with ovarian cancer were assessed by ELISPOT for recognition of nonsynonymous mutations identified by whole exome sequencing of autologous tumor.

Profound CD8+ T cell immunity elicited by sequential daily immunization with exogenous antigen plus the TLR3 agonist poly(I:C).

The development of vaccines that elicit robust CD8(+) T cell immunity has long been a subject of intense investigation. Although whole exogenous protein has not historically been considered as useful for eliciting CD8(+) T cell immunity, we report herein that whole, protein antigen is capable of eliciting profound levels of CD8(+) T cell immunity if it is administered via repeated, daily subcutaneous immunization in combination with the TLR3 agonist poly(I:C). Mice immunized for four consecutive days with 100 μg of either whole exogenous OVA or whole HPV16 E7 protein combined with 10 μg of poly(I:C) mounted remarkable antigen-specific CD8(+) T cell responses as measured by tetramer staining and ELISPOT analysis of splenocytes and peripheral blood, with up to 30% of peripheral CD8(+) T cells being antigen specific within 7-8 days of vaccination.