ABSTRACT
Obesity is a leading risk factor for progression and metastasis of many cancers1,2, yet can in some cases enhance survival3-5 and responses to immune checkpoint blockade therapies, including anti-PD-1, which targets PD-1 (encoded by PDCD1), an inhibitory receptor expressed on immune cells6-8. Although obesity promotes chronic inflammation, the role of the immune system in the obesity-cancer connection and immunotherapy remains unclear. It has been shown that in addition to T cells, macrophages can express PD-19-12. Here we found that obesity selectively induced PD-1 expression on tumour-associated macrophages (TAMs). Type I inflammatory cytokines and molecules linked to obesity, including interferon-γ, tumour necrosis factor, leptin, insulin and palmitate, induced macrophage PD-1 expression in an mTORC1- and glycolysis-dependent manner. PD-1 then provided negative feedback to TAMs that suppressed glycolysis, phagocytosis and T cell stimulatory potential. Conversely, PD-1 blockade increased the level of macrophage glycolysis, which was essential for PD-1 inhibition to augment TAM expression of CD86 and major histocompatibility complex I and II molecules and ability to activate T cells. Myeloid-specific PD-1 deficiency slowed tumour growth, enhanced TAM glycolysis and antigen-presentation capability, and led to increased CD8+ T cell activity with a reduced level of markers of exhaustion. These findings show that obesity-associated metabolic signalling and inflammatory cues cause TAMs to induce PD-1 expression, which then drives a TAM-specific feedback mechanism that impairs tumour immune surveillance. This may contribute to increased cancer risk yet improved response to PD-1 immunotherapy in obesity.
Subject(s)
Neoplasms , Obesity , Programmed Cell Death 1 Receptor , Tumor-Associated Macrophages , Animals , Female , Humans , Male , Mice , Antigen Presentation/drug effects , B7-2 Antigen/antagonists & inhibitors , B7-2 Antigen/immunology , B7-2 Antigen/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Cell Line, Tumor , Glycolysis/drug effects , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class II/immunology , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Inflammation Mediators/immunology , Inflammation Mediators/metabolism , Lymphocyte Activation , Mechanistic Target of Rapamycin Complex 1/metabolism , Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors , Mice, Inbred C57BL , Neoplasms/drug therapy , Neoplasms/immunology , Neoplasms/metabolism , Neoplasms/pathology , Obesity/immunology , Obesity/metabolism , Phagocytosis/drug effects , Programmed Cell Death 1 Receptor/metabolism , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Tumor-Associated Macrophages/immunology , Tumor-Associated Macrophages/metabolism , Tumor-Associated Macrophages/drug effectsABSTRACT
Clear cell renal cell carcinoma (ccRCC) is an aggressive cancer driven by VHL loss and aberrant HIF-2α signaling. Identifying means to regulate HIF-2α thus has potential therapeutic benefit. Acetyl-CoA synthetase 2 (ACSS2) converts acetate to acetyl-CoA and is associated with poor patient prognosis in ccRCC. Here we tested the effects of ACSS2 on HIF-2α and cancer cell metabolism and growth in ccRCC models and clinical samples. ACSS2 inhibition reduced HIF-2α levels and suppressed ccRCC cell line growth in vitro, in vivo, and in cultures of primary ccRCC patient tumors. This treatment reduced glycolytic signaling, cholesterol metabolism, and mitochondrial integrity, all of which are consistent with loss of HIF-2α. Mechanistically, ACSS2 inhibition decreased chromatin accessibility and HIF-2α expression and stability. While HIF-2α protein levels are widely regulated through pVHL-dependent proteolytic degradation, we identify a potential pVHL-independent pathway of degradation via the E3 ligase MUL1. We show that MUL1 can directly interact with HIF-2α and that overexpression of MUL1 decreased HIF-2α levels in a manner partially dependent on ACSS2. These findings identify multiple mechanisms to regulate HIF-2α stability and ACSS2 inhibition as a strategy to complement HIF-2α-targeted therapies and deplete pathogenically stabilized HIF-2α.
Subject(s)
Acetate-CoA Ligase , Basic Helix-Loop-Helix Transcription Factors , Carcinoma, Renal Cell , Gene Expression Regulation, Neoplastic , Kidney Neoplasms , Signal Transduction , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/genetics , Humans , Basic Helix-Loop-Helix Transcription Factors/metabolism , Basic Helix-Loop-Helix Transcription Factors/genetics , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Kidney Neoplasms/genetics , Cell Line, Tumor , Acetate-CoA Ligase/metabolism , Acetate-CoA Ligase/genetics , Animals , Mice , Von Hippel-Lindau Tumor Suppressor Protein/metabolism , Von Hippel-Lindau Tumor Suppressor Protein/genetics , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Protein Ligases/genetics , Neoplasm Proteins/metabolism , Neoplasm Proteins/geneticsABSTRACT
We sought to evaluate the efficacy of WEE1 inhibitor adavosertib in patients with solid tumor malignancies (cohort A) and clear cell renal cell carcinoma (ccRCC; cohort B). NCT03284385 was a parallel cohort, Simon two-stage, phase II study of adavosertib (300 mg QDAY by mouth on days 1-5 and 8-12 of each 21-day cycle) in patients with solid tumor malignancies harboring a pathogenic SETD2 mutation. The primary endpoint was the objective response rate. Correlative assays evaluated the loss of H3K36me3 by IHC, a downstream consequence of SETD2 loss, in archival tumor tissue. Eighteen patients were enrolled (9/cohort). The median age was 60 years (range 45-74). The median duration of treatment was 1.28 months (range 0-24+). No objective responses were observed in either cohort; accrual was halted following stage 1. Minor tumor regressions were observed in 4/18 (22%) evaluable patients. Stable disease (SD) was the best overall response in 10/18 (56%) patients, including three patients with SD > 4 months. One patient with ccRCC remains on treatment for >24 months. The most common adverse events of any grade were nausea (59%), anemia (41%), diarrhea (41%), and neutropenia (41%). Nine patients (50%) experienced a Grade ≥3 adverse event. Of eight evaluable archival tissue samples, six (75%) had a loss of H3K36me3 by IHC. Adavosertib failed to exhibit objective responses in SETD2-altered ccRCC and other solid tumor malignancies although prolonged SD was observed in a subset of patients. Combination approaches may yield greater depth of tumor response. SIGNIFICANCE: WEE1 inhibition with adavosertib monotherapy demonstrated limited clinical activity in patients with SETD2-altered solid tumors despite compelling preclinical data indicating a synthetic lethal effect, which did not translate into robust tumor regression. Loss of the H3K36me3 trimethylation mark caused by SETD2-deficiency was confirmed in the majority of evaluable tumors. A subset of patients derived clinical benefit as manifested by minor tumor regressions and prolonged SD.
Subject(s)
Cell Cycle Proteins , Histone-Lysine N-Methyltransferase , Protein-Tyrosine Kinases , Pyrazoles , Humans , Middle Aged , Histone-Lysine N-Methyltransferase/genetics , Male , Aged , Female , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/genetics , Cell Cycle Proteins/genetics , Cell Cycle Proteins/antagonists & inhibitors , Pyrazoles/therapeutic use , Pyrazoles/adverse effects , Pyrazoles/pharmacology , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/pathology , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Kidney Neoplasms/drug therapy , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Pyrimidinones/therapeutic use , Pyrimidinones/pharmacology , Pyrimidinones/administration & dosage , MutationABSTRACT
The tumor microenvironment is a determinant of cancer progression and therapeutic efficacy, with nutrient availability playing an important role. Although it is established that the local abundance of specific nutrients defines the metabolic parameters for tumor growth, the factors guiding nutrient availability in tumor compared to normal tissue and blood remain poorly understood. To define these factors in renal cell carcinoma (RCC), we performed quantitative metabolomic and comprehensive lipidomic analyses of tumor interstitial fluid (TIF), adjacent normal kidney interstitial fluid (KIF), and plasma samples collected from patients. TIF nutrient composition closely resembles KIF, suggesting that tissue-specific factors unrelated to the presence of cancer exert a stronger influence on nutrient levels than tumor-driven alterations. Notably, select metabolite changes consistent with known features of RCC metabolism are found in RCC TIF, while glucose levels in TIF are not depleted to levels that are lower than those found in KIF. These findings inform tissue nutrient dynamics in RCC, highlighting a dominant role of non-cancer-driven tissue factors in shaping nutrient availability in these tumors.
Cancer cells convert nutrients into energy differently compared to healthy cells. This difference in metabolism allows them to grow and divide more quickly and sometimes to migrate to different areas of the body. The environment around cancer cells known as the tumor microenvironment contains a variety of different cells and blood vessels, which are bathed in interstitial fluid. This microenvironment provides nutrients for the cancer cells to metabolize, and therefore influences how well a tumor grows and how it might respond to treatment. Recent advances with techniques such as mass spectrometry, which can measure the chemical composition of a substance, have allowed scientists to measure nutrient levels in the tumor microenvironments of mice. However, it has been more difficult to conduct such studies in humans, as well as to compare the tumor microenvironment to the healthy tissue the tumors arose from. Abbott, Ali, Reinfeld et al. aimed to fill this gap in knowledge by using mass spectrometry to measure the nutrient levels in the tumor microenvironment of 55 patients undergoing surgery to remove kidney tumors. Comparing the type and levels of nutrients in the tumor interstitial fluid, the neighboring healthy kidney and the blood showed that nutrients in the tumor and healthy kidney were more similar to each other than those in the blood. For example, both the tumor and healthy kidney interstitial fluids contained less glucose than the blood. However, the difference between nutrient composition in the tumor and healthy kidney interstitial fluids was insignificant, suggesting that the healthy kidney and its tumor share a similar environment. Taken together, the findings indicate that kidney cancer cells must adapt to the nutrients available in the kidney, rather than changing what nutrients are available in the tissue. Future studies will be required to investigate whether this finding also applies to other types of cancer. A better understanding of how cancer cells adapt to their environments may aid the development of drugs that aim to disrupt the metabolism of tumors.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Metabolomics , Tumor Microenvironment , Carcinoma, Renal Cell/blood , Carcinoma, Renal Cell/chemistry , Carcinoma, Renal Cell/pathology , Kidney/metabolism , Kidney/pathology , Lipidomics , Principal Component Analysis , Humans , Kidney Neoplasms/blood , Kidney Neoplasms/chemistry , Kidney Neoplasms/pathology , Glucose/analysisABSTRACT
SUMMARY: The NCI director presents her vision of the National Cancer Plan as an integrated framework that can help drive innovation in cancer research to speed progress toward ending cancer as we know it.
Subject(s)
Neoplasms , Humans , Neoplasms/genetics , Neoplasms/therapy , ResearchABSTRACT
Clear cell renal cell carcinoma (ccRCC) is characterized by dysregulated hypoxia signaling and a tumor microenvironment (TME) highly enriched in myeloid and lymphoid cells. Loss of the von Hippel Lindau (VHL) gene is a critical early event in ccRCC pathogenesis and promotes stabilization of HIF. Whether VHL loss in cancer cells affects immune cells in the TME remains unclear. Using Vhl WT and Vhl-KO in vivo murine kidney cancer Renca models, we found that Vhl-KO tumors were more infiltrated by immune cells. Tumor-associated macrophages (TAMs) from Vhl-deficient tumors demonstrated enhanced in vivo glucose consumption, phagocytosis, and inflammatory transcriptional signatures, whereas lymphocytes from Vhl-KO tumors showed reduced activation and a lower response to anti-programmed cell death 1 (anti-PD-1) therapy in vivo. The chemokine CX3CL1 was highly expressed in human ccRCC tumors and was associated with Vhl deficiency. Deletion of Cx3cl1 in cancer cells decreased myeloid cell infiltration associated with Vhl loss to provide a mechanism by which Vhl loss may have contributed to the altered immune landscape. Here, we identify cancer cell-specific genetic features that drove environmental reprogramming and shaped the tumor immune landscape, with therapeutic implications for the treatment of ccRCC.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Animals , Humans , Mice , Carcinogenesis/genetics , Carcinoma, Renal Cell/genetics , Cell Transformation, Neoplastic , Kidney , Kidney Neoplasms/genetics , Tumor Microenvironment , Von Hippel-Lindau Tumor Suppressor Protein/geneticsABSTRACT
The US National Cancer Act of 1971 designated the director of the National Cancer Institute as responsible for coordinating federal agencies and nonfederal organizations to make progress against cancer. As part of her role, the immediate past director of the National Cancer Institute (MMB) led the development of a National Cancer Plan that was formally released on April 3, 2023. The plan includes 8 aspirational goals "to achieve a society where every person with cancer lives a full and active life and to prevent most cancers so that few people need to face this diagnosis." Research findings provide a foundation for each goal, and research gaps are included in the strategies for meeting each goal. The President's Cancer Panel, also created by the National Cancer Act, conducted an initial assessment of progress toward the plan goals by hearing from 12 organizations at a virtual public meeting on September 7, 2023. The purpose of this commentary is to orient the scientific community to the plan and call attention to related knowledge gaps that could benefit from research.
Subject(s)
National Cancer Institute (U.S.) , Neoplasms , Humans , United States/epidemiology , Neoplasms/epidemiology , Neoplasms/prevention & control , Neoplasms/therapy , Biomedical Research/organization & administrationABSTRACT
The tumor microenvironment is a determinant of cancer progression and therapeutic efficacy, with nutrient availability playing an important role. Although it is established that the local abundance of specific nutrients defines the metabolic parameters for tumor growth, the factors guiding nutrient availability in tumor compared to normal tissue and blood remain poorly understood. To define these factors in renal cell carcinoma (RCC), we performed quantitative metabolomic and comprehensive lipidomic analyses of tumor interstitial fluid (TIF), adjacent normal kidney interstitial fluid (KIF), and plasma samples collected from patients. TIF nutrient composition closely resembles KIF, suggesting that tissue-specific factors unrelated to the presence of cancer exert a stronger influence on nutrient levels than tumor-driven alterations. Notably, select metabolite changes consistent with known features of RCC metabolism are found in RCC TIF, while glucose levels in TIF are not depleted to levels that are lower than those found in KIF. These findings inform tissue nutrient dynamics in RCC, highlighting a dominant role of non-cancer driven tissue factors in shaping nutrient availability in these tumors.
ABSTRACT
Renal cell carcinoma (RCC) and urothelial carcinoma (UC) are two of the most common genitourinary malignancies. 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG) can play an important role in the evaluation of patients with RCC and UC. In addition to the clinical utility of 18F-FDG PET to evaluate for metastatic RCC or UC, the shift in molecular imaging to focus on specific ligand-receptor interactions should provide novel diagnostic and therapeutic opportunities in genitourinary malignancies. In combination with the rise of artificial intelligence, our ability to derive imaging biomarkers that are associated with treatment selection, response assessment, and overall patient prognostication will only improve.