Disruption of the cellular pathway modulating endogenous 24-h rhythms, referred to as "the circadian clock", has been recently proven to be associated with cancer risk, development, and progression. ...This pathway operates through a complex network of transcription-translation feedback loops generated by a set of interplaying proteins. The expression of core circadian clock genes is frequently dysregulated in human tumors; however, the specific effects and underlying mechanisms seem to vary depending on the cancer types and are not fully understood. In addition, specific oncogenes may differentially induce the dysregulation of the circadian clock in tumors. Pharmacological modulation of clock components has been shown to result in specific lethality in certain types of cancer cells, and thus holds great promise as a novel anti-cancer therapeutic approach. Here we present an overview of the rationale and current evidence for targeting the clock in cancer treatment.
Breast cancer has historically been considered a non-immunogenic tumor. Multiple studies over the last 10–15 years have demonstrated that a small subset of breast cancers is immune-activated, with ...PD-L1 expression and/or TILs in the tumor microenvironment. The PD-1 inhibitor pembrolizumab in combination with chemotherapy is now approved by the US FDA for the first-line treatment of metastatic PD-L1 + triple negative breast cancer, and the PD-L1 inhibitor atezolizumab has also demonstrated clinical activity. The median progression-free survival for pembrolizumab or atezolizumab combined with chemotherapy increased with the addition of immunotherapy by 4.1 months and 2.5 months, respectively. Despite this success, there is major room for improvement. Clinical benefit is modest. Only about 40% of triple negative breast cancers are PD-L1 + , not all PD-L1 + patients with advanced triple negative breast cancer respond, and immunotherapy is not yet approved for advanced PD-L1-negative triple negative breast cancer, HER2 + breast cancer, or ER + breast cancer. It is likely that redundant pathways of immune suppression are active in breast cancer, or that important pathways of immune activation are silent. In this review, we discuss emerging strategies for targeting multiple pathways of immunoregulation in advanced breast cancer with dual immune checkpoint inhibition, bispecific antibodies, and novel antibody drug conjugates. We also discuss the potential of nanotechnology to improve the delivery of immunotherapeutics to the breast tumor microenvironment to enhance their antitumor activity.
Both tumors and aging alter the immune landscape of tissues. These interactions may play an important role in tumor progression among elderly patients and may suggest considerations for patient care. ...We leverage large-scale genomic and clinical databases to perform comprehensive comparative analysis of molecular and cellular markers of immune checkpoint blockade (ICB) response with patient age. These analyses demonstrate that aging is associated with increased tumor mutational burden, increased expression and decreased promoter methylation of immune checkpoint genes, and increased interferon gamma signaling in older patients in many cancer types studied, all of which are expected to promote ICB efficacy. Concurrently, we observe age-related alterations that might be expected to reduce ICB efficacy, such as decreases in T cell receptor diversity. Altogether, these changes suggest the capacity for robust ICB response in many older patients, which may warrant large-scale prospective study on ICB therapies among patients of advanced age.
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•We investigate the relationship of patient age and ICB therapy biomarkers•Favorable ICB biomarkers are generally more prevalent in elderly patients•The CAMA web application provides a multi-omics atlas of aging in cancer
Erbe et al. use multi-omics databases to evaluate biomarkers that are used to predict the response of patients with cancer to ICB in the context of aging. Erbe et al. find that biomarkers associated with ICB response are enriched in tumors from older patients relative to their younger counterparts.
Myeloid-derived suppressor cells (MDSC) play a prominent role in the tumor microenvironment. A quantitative understanding of the tumor-MDSC interactions that influence disease progression is ...critical, and currently lacking. We developed a mathematical model of metastatic growth and progression in immune-rich tumor microenvironments. We modeled the tumor-immune dynamics with stochastic delay differential equations and studied the impact of delays in MDSC activation/recruitment on tumor growth outcomes. In the lung environment, when the circulating level of MDSCs was low, the MDSC delay had a pronounced impact on the probability of new metastatic establishment: blocking MDSC recruitment could reduce the probability of metastasis by as much as 50%. To predict patient-specific MDSC responses, we fit to the model individual tumors treated with immune checkpoint inhibitors via Bayesian parameter inference. We reveal that control of the inhibition rate of natural killer (NK) cells by MDSCs had a larger influence on tumor outcomes than controlling the tumor growth rate directly. Posterior classification of tumor outcomes demonstrates that incorporating knowledge of the MDSC responses improved predictive accuracy from 63% to 82%. Investigation of the MDSC dynamics in an environment low in NK cells and abundant in cytotoxic T cells revealed, in contrast, that small MDSC delays no longer impacted metastatic growth dynamics. Our results illustrate the importance of MDSC dynamics in the tumor microenvironment overall and predict interventions promoting shifts toward less immune-suppressed states. We propose that there is a pressing need to consider MDSCs more often in analyses of tumor microenvironments.
The brain–gut axis, a bidirectional network between the central and enteric nervous system, plays a critical role in modulating the gastrointestinal tract function and homeostasis. Recently, ...increasing evidence suggests that neuronal signaling molecules can promote gastrointestinal cancers, however, the mechanisms remain unclear. Aberrant expression of neurotransmitter signaling genes in colorectal cancer supports the role of neurotransmitters to stimulate tumor growth and metastatic spread by promoting cell proliferation, migration, invasion, and angiogenesis. In addition, neurotransmitters can interact with immune and endothelial cells in the tumor microenvironment to promote inflammation and tumor progression. As such, pharmacological targeting of neurotransmitter signaling represent a promising novel anticancer approach. Here, we present an overview of the current evidence supporting the role of neurotransmitters in colorectal cancer biology and treatment.
Epigenetic modulators improve immune checkpoint inhibitor (ICI) efficacy and increase CD8
effector:FoxP3
regulatory T cell ratios in preclinical models. We conducted a multicenter phase I clinical ...trial combining the histone deacetylase inhibitor entinostat with nivolumab ± ipilimumab in advanced solid tumors.
Patients received an entinostat run-in (5 mg, weekly × 2) prior to the addition of ICIs. Dose escalation followed a modified 3+3 design dose level (DL)1/2: entinostat + nivolumab; DL 3/4: entinostat + nivolumab + ipilimumab. Blood and tissue samples were collected at baseline, after entinostat run-in, and after 8 weeks of combination therapy. Primary endpoints included safety and tolerability, and the recommended phase II dose (RP2D). Secondary endpoints included antitumor activity and change in tumor CD8/FoxP3 ratio pre- and post-therapy.
Thirty-three patients were treated across four dose levels. Treatment-related adverse events (AE) included fatigue (65%), nausea (41%), anemia (38%), diarrhea (26%), and anorexia (26%). Grade 3/4 AEs included fatigue (
= 7, 21%), anemia (
= 9, 27%), and neutropenia (
= 4, 12%). The RP2D was 3 mg entinostat weekly, 3 mg/kg every 2 weeks nivolumab, and 1 mg/kg every 6 weeks ipilimumab (max four doses). The objective response rate by RECIST 1.1 was 16%, including a complete response in triple-negative breast cancer. A statistically significant increase in CD8/FoxP3 ratio was seen following the addition of ICIs to entinostat, but not post-entinostat alone.
The combination of entinostat with nivolumab ± ipilimumab was safe and tolerable with expected rates of immune-related AEs. Preliminary evidence of both clinical efficacy and immune modulation supports further investigation.
Purpose
Programmed death receptor ligand-1 (PD-L1) expression and tumor mutational burden (TMB) are approved screening biomarkers for immune checkpoint inhibition (ICI) in advanced triple negative ...breast cancer. We examined these biomarkers along with characterization of the tumor microenvironment (TME) between breast tumors (BrTs), axillary metastases (AxMs), liver metastases (LvMs), non-axillary lymph node metastases, and non-liver metastases to determine differences related to site of metastatic disease.
Methods
3076 unpaired biopsies from breast cancer patients were analyzed using whole transcriptome sequencing and NextGen DNA depicting TMB within tumor sites. The PD-L1 positivity was determined with VENTANA PD-L1 (SP142) assay. The immune cell fraction within the TME was calculated by QuantiSeq and MCP-counter.
Results
Compared to BrT, more LvM samples had a high TMB (≥ 10 mutations/Mb) and fewer LvM samples had PD-L1
+
expression. Evaluation of the TME revealed that LvM sites harbored lower infiltration of adaptive immune cells, such as CD4
+
, CD8
+
, and regulatory T-cells compared with the BrT foci. We saw differences in innate immune cell infiltration in LvM compared to BrT, including neutrophils and NK cells.
Conclusions
LvMs are less likely to express PD-L1
+
tumor cells but more likely to harbor high TMB as compared to BrTs. Unlike AxMs, LvMs represent a more immunosuppressed TME and demonstrate lower gene expression associated with adaptive immunity compared to BrTs. These findings suggest biopsy site be considered when interpreting results that influence ICI use for treatment and further investigation of immune composition and biomarkers expression by metastatic site.
Immune checkpoint inhibitors have yet to significantly improve outcomes for hormone-dependent estrogen/progesterone receptor-positive breast cancer. To address this issue, there is a need for murine ...models that more closely mimic hormone receptor-positive breast cancer. In this issue, Gil Del Alcazar and colleagues provide an in-depth characterization of a Nitroso-N-methylurea-induced mammary tumor model in outbred Sprague-Dawley rats that meets these needs as it mimics the heterogeneity for mutational profiles, estrogen receptor expression, and immune evasive mechanisms observed in human breast cancer. See related article by Gil Del Alcazar et al., p. 680 (1).
Background: This evaluation emphasizes the main points of the original article 'Position paper: new insights into the immunobiology and dynamics of tumor-host interactions require adaptations of ...clinical studies' by Sprenger et al. and provides further justification for the use of an alternative approach in the design of human clinical trials for new investigational drugs in the field of immuno-oncology.Objective: Standard trial design utilizing the double blind placebo trial approach, while effective for drugs that directly treat tumors, is too costly, slow, and not effective for drugs and protocols that depend on activation of the immune system for killing of tumors.Methods/results: This paper has proposed through the use of detailed diagnostic profiling, small groups of patients with similar tumor microenvironment characteristics be grouped to determine the clinical benefit of immunological combinations that enter clinical trials. In addition, mega data from larger trials in which patients are subcategorized as above can provide the necessary data as a substitute for current double blind placebo trials which do not take into account the immune status of the host and tumor.Conclusion: There needs to be evolution of the clinical trial landscape so that it matches the exponential growth of the field of immunotherapy.
Tumor heterogeneity provides a complex challenge to cancer treatment and is a critical component of therapeutic response, disease recurrence, and patient survival. Single-cell RNA-sequencing ...(scRNA-seq) technologies have revealed the prevalence of intratumor and intertumor heterogeneity. Computational techniques are essential to quantify the differences in variation of these profiles between distinct cell types, tumor subtypes, and patients to fully characterize intratumor and intertumor molecular heterogeneity. In this study, we adapted our algorithm for pathway dysregulation, Expression Variation Analysis (EVA), to perform multivariate statistical analyses of differential variation of expression in gene sets for scRNA-seq. EVA has high sensitivity and specificity to detect pathways with true differential heterogeneity in simulated data. EVA was applied to several public domain scRNA-seq tumor datasets to quantify the landscape of tumor heterogeneity in several key applications in cancer genomics such as immunogenicity, metastasis, and cancer subtypes. Immune pathway heterogeneity of hematopoietic cell populations in breast tumors corresponded to the amount of diversity present in the T-cell repertoire of each individual. Cells from head and neck squamous cell carcinoma (HNSCC) primary tumors had significantly more heterogeneity across pathways than cells from metastases, consistent with a model of clonal outgrowth. Moreover, there were dramatic differences in pathway dysregulation across HNSCC basal primary tumors. Within the basal primary tumors, there was increased immune dysregulation in individuals with a high proportion of fibroblasts present in the tumor microenvironment. These results demonstrate the broad utility of EVA to quantify intertumor and intratumor heterogeneity from scRNA-seq data without reliance on low-dimensional visualization. SIGNIFICANCE: This study presents a robust statistical algorithm for evaluating gene expression heterogeneity within pathways or gene sets in single-cell RNA-seq data.
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