Serial circulating tumor DNA (ctDNA) monitoring is emerging as a non-invasive strategy to predict and monitor immune checkpoint blockade (ICB) therapeutic efficacy across cancer types. Yet, limited ...data exist to show the relationship between ctDNA dynamics and tumor genome and immune microenvironment in patients receiving ICB. Here, we present an in-depth analysis of clinical, whole-exome, transcriptome, and ctDNA profiles of 73 patients with advanced solid tumors, across 30 cancer types, from a phase II basket clinical trial of pembrolizumab (NCT02644369) and report changes in genomic and immune landscapes (primary outcomes). Patients stratified by ctDNA and tumor burden dynamics correspond with survival and clinical benefit. High mutation burden, high expression of immune signatures, and mutations in BRCA2 are associated with pembrolizumab molecular sensitivity, while abundant copy-number alterations and B2M loss-of-heterozygosity corresponded with resistance. Upon treatment, induction of genes expressed by T cell, B cell, and myeloid cell populations are consistent with sensitivity and resistance. We identified the upregulated expression of PLA2G2D, an immune-regulating phospholipase, as a potential biomarker of adaptive resistance to ICB. Together, these findings provide insights into the diversity of immunogenomic mechanisms that underpin pembrolizumab outcomes.
Abstract A breadth of studies have demonstrated the importance of GITR–GITRL in diverse immune processes. However, only a limited number of studies to date have attributed the effects of GITR/GITRL ...to specific cell types. Moreover, the context-dependent role of GITR/GITRL in different models makes the consequences of GITR ligation difficult to generalize. There is a significant interest in the therapeutic application of GITR agonists and antagonists in human disease. Thus, the field must come to a consensus regarding the cell type-specific and physiological effects of GITR in different disease states. Here we attempt to summarize the extensive literature on GITR, to synthesize a more cohesive picture of the role of GITR/GITRL in immunity, and to identify areas that require clarification.
Immune checkpoint blockade (ICB) provides clinical benefit to a subset of patients with cancer. However, existing biomarkers do not reliably predict treatment response across diverse cancer types. ...Limited data exist to show how serial circulating tumor DNA (ctDNA) testing may perform as a predictive biomarker in patients receiving ICB. We conducted a prospective phase II clinical trial to assess ctDNA in five distinct cohorts of patients with advanced solid tumors treated with pembrolizumab (NCT02644369). We applied bespoke ctDNA assays to 316 serial plasma samples obtained at baseline and every three cycles from 94 patients. Baseline ctDNA concentration correlated with progression-free survival, overall survival, clinical response and clinical benefit. This association became stronger when considering ctDNA kinetics during treatment. All 12 patients with ctDNA clearance during treatment were alive with median 25 months follow up. This study demonstrates the potential for broad clinical utility of ctDNA-based surveillance in patients treated with ICB.
CD4 T cells are critical for control of persistent infections; however, the key signals that regulate CD4 T help during chronic infection remain incompletely defined. While several studies have ...addressed the role of inhibitory receptors and soluble factors such as PD-1 and IL-10, significantly less work has addressed the role of T cell co-stimulatory molecules during chronic viral infection. Here we show that during a persistent infection with lymphocytic choriomeningitis virus (LCMV) clone 13, mice lacking the glucocorticoid-induced tumor necrosis factor receptor related protein (GITR) exhibit defective CD8 T cell accumulation, increased T cell exhaustion and impaired viral control. Differences in CD8 T cells and viral control between GITR+/+ and GITR-/- mice were lost when CD4 T cells were depleted. Moreover, mixed bone marrow chimeric mice, as well as transfer of LCMV epitope-specific CD4 or CD8 T cells, demonstrated that these effects of GITR are largely CD4 T cell-intrinsic. GITR is dispensable for initial CD4 T cell proliferation and differentiation, but supports the post-priming accumulation of IFNγ+IL-2+ Th1 cells, facilitating CD8 T cell expansion and early viral control. GITR-dependent phosphorylation of the p65 subunit of NF-κB as well as phosphorylation of the downstream mTORC1 target, S6 ribosomal protein, were detected at day three post-infection (p.i.), and defects in CD4 T cell accumulation in GITR-deficient T cells were apparent starting at day five p.i. Consistently, we pinpoint IL-2-dependent CD4 T cell help for CD8 T cells to between days four and eight p.i. GITR also increases the ratio of T follicular helper to T follicular regulatory cells and thereby enhances LCMV-specific IgG production. Together, these findings identify a CD4 T cell-intrinsic role for GITR in sustaining early CD8 and late humoral responses to collectively promote control of chronic LCMV clone 13 infection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Immunotherapies targeting PD-1/PD-L1 are now widely used in the clinic to treat a variety of malignancies. While most of the research on T cell exhaustion and PD-1 blockade has been focused on ...conventional αβ T cells, the contribution of innate-like T cells such as γδ T cells to anti-PD-1/PD-L1 mediated therapy is limited. Here we show that tumor reactive γδ T cells respond to PD-1 blockade in a Merkel cell carcinoma (MCC) patient experiencing a complete response to therapy. We find clonally expanded γδ T cells in the blood and tumor after pembrolizumab treatment, and this Vγ2Vδ1 clonotype recognizes Merkel cancer cells in a TCR-dependent manner. Notably, the intra-tumoral γδ T cells in the MCC patient are characterized by higher expression of PD-1 and TIGIT, relative to conventional CD4 and CD8 T cells. Our results demonstrate that innate-like T cells could also contribute to an anti-tumor response after PD-1 blockade.
Patients diagnosed with high-grade serous ovarian cancer (HGSOC) who received initial debulking surgery followed by platinum-based chemotherapy can experience highly variable clinical responses. A ...small percentage of women experience exceptional long-term survival (long term (LT), 10+ years), while others develop primary resistance to therapy and succumb to disease in less than 2 years (short term (ST)). To improve clinical management of HGSOC, there is a need to better characterize clinical and molecular profiles to identify factors that underpin these disparate survival responses.
To identify clinical and tumor molecular biomarkers associated with exceptional clinical response or resistance, we conducted an integrated clinical, exome, and transcriptome analysis of 41 primary tumors from LT (n = 20) and ST (n = 21) HGSOC patients.
Younger age at diagnosis, no residual disease post debulking surgery and low CA125 levels following surgery and chemotherapy were clinical characteristics of LT. Tumors from LT survivors had increased somatic mutation burden (median 1.62 vs. 1.22 non-synonymous mutations/Mbp), frequent BRCA1/2 biallelic inactivation through mutation and loss of heterozygosity, and enrichment of activated CD4+, CD8+ T cells, and effector memory CD4+ T cells. Characteristics of ST survival included focal copy number gain of CCNE1, lack of BRCA mutation signature, low homologous recombination deficiency scores, and the presence of ESR1-CCDC170 gene fusion.
Our findings suggest that exceptional long- or short-term survival is determined by a concert of clinical, molecular, and microenvironment factors.
TRAF1 is a signaling adaptor known for its role in tumor necrosis factor receptor-induced cell survival. Here we show that monocytes from healthy human subjects with a rheumatoid arthritis-associated ...single-nucleotide polymorphism (SNP) in the TRAF1 gene express less TRAF1 protein but greater amounts of inflammatory cytokines in response to lipopolysaccharide (LPS). The TRAF1 MATH domain binds directly to three components of the linear ubiquitination (LUBAC) complex, SHARPIN, HOIP and HOIL-1, to interfere with the recruitment and linear ubiquitination of NEMO. This results in decreased NF-κB activation and cytokine production, independently of tumor necrosis factor. Consistent with this, Traf1
mice show increased susceptibility to LPS-induced septic shock. These findings reveal an unexpected role for TRAF1 in negatively regulating Toll-like receptor signaling, providing a mechanistic explanation for the increased inflammation seen with a disease-associated TRAF1 SNP.
Checkpoint blockade is a type of immunotherapy that has shown unprecedented success in treating many cancers (1), particularly blockade of the T cell checkpoint protein called programmed cell death-1 ...(PD-1). This has created a unique situation in which clinical studies have outpaced efforts at the bench. As such, reliable predictive biomarkers have not yet been identified that define who will benefit from this method of treatment, and there is only a partial understanding of the mechanisms of sensitivity or resistance to immunotherapy. On pages 1428 and 1423 of this issue, Hui et al. (2) and Kamphorst et al. (3), respectively, elucidate important mechanisms of checkpoint blockade by demonstrating that PD-1 exerts its primary effect of dampening T cell activation by regulating a T cell receptor costimulatory molecule called cluster of differentiation 28 (CD28).
Summary
Immunity to viruses must be tightly controlled to avoid pathology. Receptors and ligands of the tumor necrosis factor (TNF) family play important roles in controlling lymphocyte activation ...and survival during an immune response. The role of specific TNF receptor (TNFR) family members in antiviral immunity depends on the stage of the immune response and can vary with the virus type and its virulence. Here, we focus on five members of the TNFR family that are prominently expressed on CD8+ T cells during viral infections, namely, 4‐1BB (CD137), CD27, OX40 (CD134), GITR, and TNFR2. 4‐1BB, CD27, OX40, and GITR have primarily prosurvival roles for CD8+ T cells during viral infection, although under some circumstances 4‐1BB, GITR, or CD27 signals can limit immunity. Although TNFR2 can be costimulatory under some circumstances, its main role in CD8+ T‐cell responses during viral infection appears to be in contraction of the response. Several TNF family ligands are being explored as adjuvants for viral vaccines, and agonistic antibodies to TNFR family members are being investigated for immunotherapy of chronic viral infection alone and in combination with checkpoint blockade. Such therapies will require thorough and specific optimization to avoid pathology induced by hyperstimulation of these pathways.
•Limited evidence for optimal sequencing of systemic therapies in prostate cancer.•In Ontario (between 2010-2018), ARATs were the most common treatment for mCRPC.•After ARAT failure, sequential ARAT ...or taxane use provide similar survival outcomes.•Data may inform optimal oral and IV therapy sequencing, useful for COVID pandemic.
We sought to quantify mCRPC patient treatment patterns and survival across multiple lines of therapy after prior androgen-receptor-axis-targeted therapy (ARAT) failure.
Individuals diagnosed with prostate cancer between 2010 and 2018 were identified in the Ontario Cancer Registry (OCR). An algorithm was created to identify patients with mCRPC that was aligned to Prostate Cancer Clinical Trials Working Group 3 criteria (PCWG3) and validated with Canadian clinical experts. In the mCRPC setting, treatment patterns were assessed by line of therapy, and survival was calculated from treatment initiation until death or lost to follow-up.
64,484 men were diagnosed withprostate cancer in Ontario between 2010 and 2018with 5,588 men assessed to have mCRPC and 2,970 (53%) of those received first-line systemic treatment. Across the first-, second- and third-line of therapy, ARATs (abiraterone and enzalutamide) were the most used therapies. Survival for mCRPC patients treated with ARATs in first-, second- and third-line were 13.0 (95% CI, 11.6 – 14.5), 11.5 (95% CI, 10.1 – 13.4) and 8.9 (95% CI, 7.4 – 10.2) months, respectively. Survival for mCRPC patients treated with taxanes in first, second- and third-line were 16.7 (95% CI, 14.8 – 18.0), 11.3 (95% CI, 10.1 – 12.5) and 7.8 (95% CI, 6.5 – 10.6) months, respectively. No statistical difference in overall survival was found between taxanes and ARATs.
In this analysis of a large retrospective cohort of Canadian men with mCRPC, we found that survival in patients treated with ARATs and taxanes was fairly similar across all lines of therapy. Importantly, this trend was maintained in ARAT-exposed patients, where sequential ARAT and taxanes offered similar survival. These data may help inform optimal sequencing of therapies in mCRPC.
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