Tumour-intrinsic PDL1 signals regulate the Chk2 DNA damage response in cancer cells and mediate resistance to Chk1 inhibitors.

Background: Aside from the canonical role of PDL1 as a tumour surface-expressed immune checkpoint molecule, tumour-intrinsic PDL1 signals regulate non-canonical immunopathological pathways mediating treatment resistance whose significance, mechanisms, and therapeutic targeting remain incompletely understood. Recent reports implicate tumour-intrinsic PDL1 signals in the DNA damage response (DDR), including promoting homologous recombination DNA damage repair and mRNA stability of DDR proteins, but many mechanistic details remain undefined.

Methods: We genetically depleted PDL1 from transplantable mouse and human cancer cell lines to understand consequences of tumour-intrinsic PDL1 signals in the DNA damage response.

Role of cfDNA and ctDNA to improve the risk stratification and the disease follow-up in patients with endometrial cancer: towards the clinical application.

Background: There has been a rise in endometrial cancer (EC) incidence leading to increased mortality. To counter this trend, improving the stratification of post-surgery recurrence risk and anticipating disease relapse and treatment resistance is essential. Liquid biopsy analyses offer a promising tool for these clinical challenges, though the best strategy for applying them in EC must be defined.

Botensilimab, an Fc-Enhanced Anti-CTLA-4 Antibody, Is Effective against Tumors Poorly Responsive to Conventional Immunotherapy.

This study reveals that Fc-enhanced anti-CTLA-4 harnesses novel mechanisms to overcome the limitations of conventional anti-CTLA-4, effectively treating poorly immunogenic and treatment-refractory cancers. Our findings support the development of a new class of immuno-oncology agents, capable of extending clinical benefit to patients with cancers resistant to current immunotherapies.

Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial.

Microsatellite stable metastatic colorectal cancer (MSS mCRC; mismatch repair proficient) has previously responded poorly to immune checkpoint blockade. Botensilimab (BOT) is an Fc-enhanced multifunctional anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody designed to expand therapy to cold/poorly immunogenic solid tumors, such as MSS mCRC. BOT with or without balstilimab (BAL; anti-PD-1 antibody) is being evaluated in an ongoing expanded phase 1 study.

Pharmacological inhibition of the LIF/LIFR autocrine loop reveals vulnerability of ovarian cancer cells to ferroptosis.

Of all gynecologic cancers, epithelial-ovarian cancer (OCa) stands out with the highest mortality rates. Despite all efforts, 90% of individuals who receive standard surgical and cytotoxic therapy experience disease recurrence. The precise mechanism by which leukemia inhibitory factor (LIF) and its receptor (LIFR) contribute to the progression of OCa remains unknown.

Targeting intracellular oncoproteins with dimeric IgA promotes expulsion from the cytoplasm and immune-mediated control of epithelial cancers.

Dimeric IgA (dIgA) can move through cells via the IgA/IgM polymeric immunoglobulin receptor (PIGR), which is expressed mainly on mucosal epithelia. Here, we studied the ability of dIgA to target commonly mutated cytoplasmic oncodrivers. Mutation-specific dIgA, but not IgG, neutralized KRAS within ovarian carcinoma cells and expelled this oncodriver from tumor cells.

Crucial roles of the BRCA1-BARD1 E3 ubiquitin ligase activity in homology-directed DNA repair.

The tumor-suppressor breast cancer 1 (BRCA1) in complex with BRCA1-associated really interesting new gene (RING) domain 1 (BARD1) is a RING-type ubiquitin E3 ligase that modifies nucleosomal histone and other substrates. The importance of BRCA1-BARD1 E3 activity in tumor suppression remains highly controversial, mainly stemming from studying mutant ligase-deficient BRCA1-BARD1 species that we show here still retain significant ligase activity. Using full-length BRCA1-BARD1, we establish robust BRCA1-BARD1-mediated ubiquitylation with specificity, uncover multiple modes of activity modulation, and construct a truly ligase-null variant and a variant specifically impaired in targeting nucleosomal histones.

Considerations and Approaches for Cancer Immunotherapy in the Aging Host.

Advances in cancer immunotherapy are improving treatment successes in many distinct cancer types. Nonetheless, most tumors fail to respond. Age is the biggest risk for most cancers, and the median population age is rising worldwide.

Ascites-Derived Organoids to Depict Platinum Resistance in Gynaecological Serous Carcinomas.

Gynaecological serous carcinomas (GSCs) constitute a distinctive entity among female tumours characterised by a very poor prognosis. In addition to late-stage diagnosis and a high rate of recurrent disease associated with massive peritoneal carcinomatosis, the systematic acquisition of resistance to first-line chemotherapy based on platinum determines the unfavourable outcome of GSC patients. To explore the molecular mechanisms associated with platinum resistance, we generated patient-derived organoids (PDOs) from liquid biopsies of GSC patients.

Hippocampal and amygdala volumes vary with residential proximity to toxicants at Birmingham, Alabama's 35th Avenue Superfund site.

Exposure to environmental toxicants have serious implications for the general health and well-being of children, particularly during pivotal neurodevelopmental stages. The Environmental Protection Agency's (EPA) Superfund program has identified several areas (Superfund sites) across the United States with high levels of environmental toxicants, which affect the health of many residents in nearby communities. Exposure to these environmental toxicants has been linked to changes in the structure and function of the brain.

The complementarity of DDR, nucleic acids and anti-tumour immunity.

Immune checkpoint blockade (ICB) immunotherapy is a first-line treatment for selected cancers, yet the mechanisms of its efficacy remain incompletely understood. Furthermore, only a minority of patients with cancer benefit from ICB, and there is a lack of fully informative treatment response biomarkers. Selectively exploiting defects in DNA damage repair is also a standard treatment for cancer, spurred by enhanced understanding of the DNA damage response (DDR).

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of gynecologic cancer.

Advanced gynecologic cancers have historically lacked effective treatment options. Recently, immune checkpoint inhibitors (ICIs) have been approved by the US Food and Drug Administration for the treatment of cervical cancer and endometrial cancer, offering durable responses for some patients. In addition, many immunotherapy strategies are under investigation for the treatment of earlier stages of disease or in other gynecologic cancers, such as ovarian cancer and rare gynecologic tumors.

Immune checkpoint expression and relationships to anti-PD-L1 immune checkpoint blockade cancer immunotherapy efficacy in aged versus young mice.

Introduction: Aging is the biggest cancer risk, and immune checkpoint (IC) inhibition (ICI) is a revolutionary cancer immunotherapy approach. Nonetheless, there are limited preclinical/clinical data regarding aging effects on ICI outcomes or age effects on IC expression in different organs or tumors.

Methods: Flow cytometry assessed IC on immune and non-immune cells in various organs in young and aged BL6 mice.

Pharmacological tumor PDL1 depletion with chlorambucil treats ovarian cancer and melanoma: improves antitumor immunity and renders anti-PDL1-resistant tumors anti-PDL1-sensitive through NK cell effects.

Background: Tumor intracellular programmed cell death ligand-1 (PDL1) mediates pathologic signals that regulate clinical treatment responses distinctly from surface-expressed PDL1 targeted by αPDL1 immune checkpoint blockade antibodies.

Methods: We performed a drug screen for tumor cell PDL1 depleting drugs that identified Food and Drug Administration (FDA)-approved chlorambucil and also 9-[2-(phosphonomethoxy)ethyl] guanine. We used in vitro and in vivo assays to evaluate treatment and signaling effects of pharmacological tumor PDL1 depletion focused on chlorambucil as FDA approved, alone or plus αPDL1.

PRC2-Mediated Epigenetic Suppression of Type I IFN-STAT2 Signaling Impairs Antitumor Immunity in Luminal Breast Cancer.

Unlabelled: The immunosuppressive tumor microenvironment in some cancer types, such as luminal breast cancer, supports tumor growth and limits therapeutic efficacy. Identifying approaches to induce an immunostimulatory environment could help improve cancer treatment. Here, we demonstrate that inhibition of cancer-intrinsic EZH2 promotes antitumor immunity in estrogen receptor α-positive (ERα+) breast cancer.

Belly Fat Weakens Immune Fitness.

Much work has been done to reduce cancer immunosuppression through inhibiting soluble proteins, surface molecules, and suppressive cells. This article shows an important role for the lipid lysophosphatidic acid, whose suppression shows promise as a novel cancer immunotherapeutic, demonstrated in ovarian cancer. See related article by Chae et al.

Selective delipidation of Mycobacterium bovis BCG retains antitumor efficacy against non-muscle invasive bladder cancer.

Purpose: Repeated instillations of bacillus Calmette et Guérin (BCG) are the gold standard immunotherapeutic treatment for reducing recurrence for patients with high-grade papillary non-muscle invasive bladder cancer (NMIBC) and for eradicating bladder carcinoma-in situ. Unfortunately, some patients are unable to tolerate BCG due to treatment-associated toxicity and bladder removal is sometimes performed for BCG-intolerance. Prior studies suggest that selectively delipidated BCG (dBCG) improves tolerability of intrapulmonary delivery reducing tissue damage and increasing efficacy in preventing Mycobacterium tuberculosis infection in mice.

Modulation of autophagy: a Phase II study of vorinostat plus hydroxychloroquine versus regorafenib in chemotherapy-refractory metastatic colorectal cancer (mCRC).

Background: In metastatic colorectal cancer (mCRC), regorafenib (RGF), a multi-kinase inhibitor with angiogenic inhibition has modest effects on survival. We reported that autophagy modulation using hydroxychloroquine (HCQ), enhances the anticancer activity of the histone deacetylase inhibitor, vorinostat (VOR), in mCRC, is well tolerated, and has comparable activity to RGF. Thus, we conducted a prospective study of VOR/HCQ versus RGF in mCRC.

Pharmacologic Tumor PDL1 Depletion with Cefepime or Ceftazidime Promotes DNA Damage and Sensitivity to DNA-Damaging Agents.

The interaction between tumor surface-expressed PDL1 and immune cell PD1 for the evasion of antitumor immunity is well established and is targeted by FDA-approved anti-PDL1 and anti-PD1 antibodies. Nonetheless, recent studies highlight the immunopathogenicity of tumor-intrinsic PDL1 signals that can contribute to the resistance to targeted small molecules, cytotoxic chemotherapy, and αPD1 immunotherapy. As genetic PDL1 depletion is not currently clinically tractable, we screened FDA-approved drugs to identify those that significantly deplete tumor PDL1.

Ovarian cancer immunogenicity is governed by a narrow subset of progenitor tissue-resident memory T cells.

Despite repeated associations between T cell infiltration and outcome, human ovarian cancer remains poorly responsive to immunotherapy. We report that the hallmarks of tumor recognition in ovarian cancer-infiltrating T cells are primarily restricted to tissue-resident memory (TRM) cells. Single-cell RNA/TCR/ATAC sequencing of 83,454 CD3CD8CD103CD69 TRM cells and immunohistochemistry of 122 high-grade serous ovarian cancers shows that only progenitor (TCF1) tissue-resident T cells (TRM cells), but not recirculating TCF1 T cells, predict ovarian cancer outcome.

Tumor Intrinsic PD-L1 Promotes DNA Repair in Distinct Cancers and Suppresses PARP Inhibitor-Induced Synthetic Lethality.

Unlabelled: BRCA1-mediated homologous recombination is an important DNA repair mechanism that is the target of FDA-approved PARP inhibitors, yet details of BRCA1-mediated functions remain to be fully elucidated. Similarly, immune checkpoint molecules are targets of FDA-approved cancer immunotherapies, but the biological and mechanistic consequences of their application are incompletely understood. We show here that the immune checkpoint molecule PD-L1 regulates homologous recombination in cancer cells by promoting BRCA1 nuclear foci formation and DNA end resection.

Programmed death ligand 1 signals in cancer cells.

The paradigm of surface-expressed programmed death ligand 1 (PDL1) signalling to immune cell programmed death 1 (PD1) to inhibit antitumour immunity has helped to develop effective and revolutionary immunotherapies using antibodies blocking these cell-extrinsic interactions. The recent discovery of cancer cell-intrinsic PDL1 signals has broadened understanding of pathologic tumour PDL1 signal consequences that now includes control of tumour growth and survival pathways, stemness, immune effects, DNA damage responses and gene expression regulation. Many such effects are PD1-independent.

TGF-β-mediated silencing of genomic organizer SATB1 promotes Tfh cell differentiation and formation of intra-tumoral tertiary lymphoid structures.

The immune checkpoint receptor PD-1 on T follicular helper (Tfh) cells promotes Tfh:B cell interactions and appropriate positioning within tissues. Here, we examined the impact of regulation of PD-1 expression by the genomic organizer SATB1 on Tfh cell differentiation. Vaccination of CD4Satb1 mice enriched for antigen-specific Tfh cells, and TGF-β-mediated repression of SATB1 enhanced Tfh differentiation of human T cells.

IgA-Dominated Humoral Immune Responses Govern Patients' Outcome in Endometrial Cancer.

Unlabelled: Recent studies suggest that B cells could play an important role in the tumor microenvironment. However, the role of humoral responses in endometrial cancer remains insufficiently investigated. Using a cohort of 107 patients with different histological subtypes of endometrial carcinoma, we evaluated the role of coordinated humoral and cellular adaptive immune responses in endometrial cancer.