The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.
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- IL-1β+ macrophages fuel pathogenic inflammation in pancreatic cancer
- Deterministic reprogramming of neutrophils within tumors
- A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer
- Manipulating mitochondrial electron flow enhances tumor immunogenicity
- Rapid adaptation to CDK2 inhibition exposes intrinsic cell-cycle plasticity
- Acquisition of suppressive function by conventional T cells limits antitumor immunity upon Treg depletion
- Cooperative CAR targeting to selectively eliminate AML and minimize escape
- DNA hypomethylation silences anti-tumor immune genes in early prostate cancer and CTCs
- Immune evasion of dormant disseminated tumor cells is due to their scarcity and can be overcome by T cell immunotherapies
- Early-Stage Breast Cancer Detection in Breast Milk
1IL-1β+ macrophages fuel pathogenic inflammation in pancreatic cancer
Caronni, N., La Terza, F., Vittoria, F.M, Barbiera, G. et al. Nature. 623, pages 415–422 (2023).
doi: doi.org/10.1038/s41586-023-06685-2.
Summary of the findings
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with few therapeutic options. Tissue damage and the ensuing inflammatory responses are known to favor pancreatic tumorigenesis by cooperating with oncogenic mutations in epithelial cells. In this article, the authors leverage advanced genomic techniques to elucidate pathogenic programs underlying tumor-promoting inflammation in PDAC. They identified a population of tumor- associated macrophages (TAMs) expressing the cytokine interleukin-1β (IL-1β) – hence termed IL-1β+ TAMs – able to stimulate inflammatory reprogramming and consequently increase the pathogenic potential of tumor cells. IL-1β+ TAMs originate from PDAC-infiltrating monocytes upon exposure to the lipid mediator prostaglandin E2 (PGE2) in the tumor microenvironment. A key finding of the study is the physical proximity between IL-1β+ TAMs and a subset of tumor cells expressing an IL-1β response signature (T1RS) in PDAC patients, highlighting a local interaction between these cells that foster tumor growth. The authors also showed that inflammatory reprogramming of epithelial cells is an early event in pancreatic tumorigenesis upon oncogenic mutations and tissue damage.
Future impact
This work identifies the PGE2-IL-1β axis as a physiological response to injury whose cooptation in cancer may support disease initiation or progression. Targeting the PGE2-IL-1β could prove beneficial as combinatorial immunotherapy for patients with advanced PDAC, as well as preventive treatment for individuals at risk.
2Deterministic reprogramming of neutrophils within tumors
Ng M. S.F., Kwok, I., Tan, L., Shi, C. et al. Science. 383 (6679), eadf6493 (2024).
doi: doi.org/10.1126/science.adf6493.
Summary of the findings
Diverse neutrophils populations varying by maturation stages, surface marker expression and transcriptional profiles infiltrate the tumor and are associated with poorer patient outcomes in cancer. Yet, how these different neutrophil states are coordinated into a unified pro-tumoral neutrophil response remains undefined. Using a mouse model of orthotopic pancreatic cancer, Ng et al. demonstrate that neutrophils undergo further epigenetic and transcriptional reprogramming upon entry into the tumor. This mechanism thus ensures neutrophils of various tissue origins or maturation stages eventually converge into a long-lived population with potent pro-angiogenic function within the tumor. Residing at a unique hypoxic-glycolytic tumor niche, reprogrammed neutrophils are optimally located to promote angiogenesis in hypoxic and nutrient-poor tumor regions. Specifically, they expressed high levels of vascular endothelial growth factor alpha (VEGFα), which significantly enhanced blood vessel formation within the tumor core and accelerated tumor growth. Depleting reprogrammed neutrophils or blocking their angiogenic function then inhibits this growth enhancement effect. The presence of neutrophil reprogramming was also observed in human cancer, where the reprogrammed neutrophil signature was associated with reduced overall survival in pancreatic cancer and other solid tumors. This work highlights the untapped possibilities of targeting pro-tumoral neutrophil responses to enhance cancer immunotherapy.
Neutrophils undergo reprogramming upon tumor entry, following a common path which unites their different functional states into a single pro-tumoral phenotype which can be specifically targeted. Importantly, this study provides evidence that this process is conserved in human solid tumors. This suggests that targeting reprogrammed neutrophils could be a new and viable therapeutic approach to inhibit angiogenesis and tumor growth in human cancer. Further studies facilitating the discovery of transcription factors, as well as tumor-derived factors, that mediate neutrophil reprogramming as well as their acquisition of pro-angiogenic function, represent important goals for the field to advance this process.
3A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer
Chitty, J.L. et al. Nat. Cancer 4, pages 1326–1344 (2023).
doi: doi.org/10.1038/s43018-023-00614-y.
Summary of the findings
Chemotherapy is the standard-of-care for pancreatic cancer patients, but over time it becomes ineffective due to a tumour scarring response (desmoplasia) elicited by the treatment. This desmoplasia is rich in fibrillar collagens, and acts to reinforce oncogenic signalling, accelerate progression, and protect the tumour from further rounds of treatment. It is thought that tumour desmoplasia contributes significantly to the poor survival rates of pancreatic cancer patients.
Lysyl oxidases catalyse crosslinking of collagen and are fundamental to the deposition and stabilisation of fibrillar collagens. In several solid cancers, lysyl oxidases are prognostic biomarkers since they are upregulated during tumour progression and further elevated during therapy-induced tumour desmoplasia. As such, targeting them is a promising avenue of research that has yet to be deployed in the clinic.
This work presents the development and validation of a novel, first-in-class mechanism-based pan-lysyl oxidase inhibitor (PXS-5505). It demonstrates that PXS-5505 functions as a bona fide anti-fibrotic agent to decrease chemotherapy-induced tumour desmoplasia and potentiate the efficacy of chemotherapy in pancreatic cancer to improve survival.
Future impact
The poor survival rates facing pancreatic cancer patients mean that novel treatment avenues are needed. Anti-stromal therapies that co-target tumour desmoplasia offer a significant translational impact for enhancing already approved therapy efficacy and improving patient outcome. PXS-5505 is an orally bioavailable, well tolerated, safe and effective mechanistic inhibitor of lysyl oxidase activity, which is currently in Phase 2 studies for haematological malignancies. Our findings present the rationale for including a pan-lysyl oxidase inhibitor aimed at eliciting a reduction in therapy-induced tumour desmoplasia to potentiate efficacy of chemotherapy in the treatment of pancreatic ductal adenocarcinoma patients.
4Manipulating mitochondrial electron flow enhances tumor immunogenicity
Mangalhara, K. C., Varanasi, S. K., et al. Science 381, pages 1316-1323 (2023).
doi: doi.org/10.1126/science.abq1053.
Summary and graphical abstract by Alexandra Boitor, EACR Scientific Officer
Summary of the findings
Cancer growth relies on metabolic plasticity, which is provided, in part, by the mitochondrial tricarboxylic acid cycle and electron transport chain.
In this paper, the authors looked at how this could be leveraged to hinder cancer progression.
Mangalhara, Varanasi et al. noticed that the knockdown of the electron transport chain complex C II in melanoma cells leads to a
substantial decrease in tumour growth. Lack of complex C II induces accumulation of mitochondrial succinate which in turn modulates the tumour epigenetic landscape leading to changes in protein transcription. As a consequence, MHC-I antigen presentation is increased leading to a strong antitumour immune response carried by CD8+ T cells. Further on, the authors of this pa
per investigated if rewiring of the electron transport chain towards favouring the use of complex C I over complex C II could increase
succinate levels to a level that would trigger an anti-tumoral immune reaction, whilst maintaining the electron chain activity and ATP production. Knockout of methylation-controlled J protein (MCJ), a protein from the mitochondrial inner membrane that endogenously interacts with C I, leads to reduced C II activity and subsequent increase in succinate levels, culminating in decreased tumour growth due to immune cell infiltration. These results indicate that discrete rewiring of the electron transport chain could be considered for turning cold tumours hot and hence improving immunotherapy efficiency.
5Rapid adaptation to CDK2 inhibition exposes intrinsic cell-cycle plasticity
Arora, M., Moser, J., Hoffman, T. E., Watts L. P. et al. Cell 186(12), pages 2628-2643.E21 (2023).
doi: doi.org/10.1016/j.cell.2023.05.013.
Summary of the findings
CDK2 is a core cell-cycle kinase that phosphorylates many substrates to drive progression through the cell cycle. CDK2 is hyperactivated in multiple cancers and is therefore an attractive therapeutic target. Here, we use several CDK2 inhibitors in clinical development to interrogate CDK2 substrate phosphorylation, cell-cycle progression, and drug adaptation in preclinical models. Whereas CDK1 is known to compensate for loss of CDK2 in Cdk2-/- mice, this is not true for acute inhibition of CDK2. Upon CDK2 inhibition, cells exhibit a rapid loss of substrate phosphorylation that rebounds within several hours. CDK4/6 activity backstops inhibition of CDK2 and sustains the proliferative program by maintaining Rb1 hyper-phosphorylation, active E2F transcription, and Cyclin A2 expression, enabling re-activation of CDK2 in the presence of drug. Our results augment our understanding of CDK plasticity and indicate that co-inhibition of CDK2 and CDK4/6 may be required to suppress adaptation to CDK2 inhibitors currently under clinical assessment.
**This abstract and figure were published in Cell, Volume 186, Issue 12, Arora, M. et al., Rapid adaptation to CDK2 inhibition exposes intrinsic cell-cycle plasticity, 2628 – 2643.e21, Copyright Elsevier (2023).
6Acquisition of suppressive function by conventional T cells limits antitumor immunity upon Treg depletion
Whiteside, S.K. et al. Sci. Immunol. 8(90), peabo5558 (2023).
doi: doi.org/10.1126/sciimmunol.abo5558.
Summary of the findings
Cancer immunotherapy has revolutionized the treatment of cancer. Breakthrough therapies, particularly those targeting immune checkpoints PD-1 and CTLA-4, have transformed the outlook for many cancer patients. However, not all patients respond to these treatments. Regulatory T (Treg) cells are powerful immunosuppressive cells which limit a patient’s immune response to cancer. As a consequence, targeting Treg cells has been a focus for researchers seeking to enhance immune responses against tumors. However, clinical trials targeting Treg cells have had limited clinical efficacy prompting a deeper investigation into their role. Whiteside et al., demonstrated that that CD4+ Foxp3− conventional T (Tconv) cells acquire suppressive function upon depletion of Foxp3+ Treg cells, limiting therapeutic efficacy. Foxp3− Tconv cells within tumors adopt a Treg cell–like transcriptional profile upon ablation of Treg cells and acquire the ability to suppress T cell activation and proliferation ex vivo. Suppression was dependent on the immunosuppressive cytokine IL-10 and was enriched in Tconv cells expressing the chemokine receptor CCR8. Resistance to Treg cell depletion could be prevented through conditional deletion of Il10 in T cells or cotreatment with IL-10R blocking antibodies. This unexpected finding challenges the previous understanding that focusing solely on Treg cells could yield substantial therapeutic benefits.
Future impact
The study not only underscores the complexity of the immune system’s response to cancer but also opens new avenues for treatment. Acquisition of a Treg cell–like transcriptional profile by Tconv cells upon Treg cell ablation suggests that in practice there are very few molecules whose targeting will enable highly specific depletion of Treg cells within tumors. A question raised by this study is whether specific depletion of Treg cells is desirable rather than the targeting of molecules shared by Treg cells and cells with compensatory suppressive function induced upon Treg cell depletion. The research provides new targets for overcoming resistance to Treg depleting immunotherapies.
7Cooperative CAR targeting to selectively eliminate AML and minimize escape
Haubner, S. et al. Cancer Cell 41(11), 1871-1891.e6 (2023).
doi: doi.org/10.1016/j.ccell.2023.09.010.
Summary and graphical abstract by Alexandra Boitor, EACR Scientific Officer
Summary of the findings
Currently, the only curative therapy for Acute Myeloid Leukemia (AML) is hematopoietic stem cell transplantation, which has increased treatment-related mortality. Moreover, relapse or refractory disease is common, to a great degree due to disease heterogeneity. Therefore, there’s an acute need for new treatment approaches. CAR therapies have been proposed and tested; however, they’ve been largely ineffective due to increased disease heterogeneity and a high degree of similarity between leukemic cells and normal hematopoietic stem/ progenitor cells (HSPCs).
In this paper, Haubner et al. quantitatively profiled the expression of surface target proteins in bone marrow and peripheral blood samples from healthy individuals and AML patients with diverse genetic subtypes aiming to develop a combinatorial CAR therapy strategy. The authors of this paper identified differential expression of ADGRE2 and CLEC12A between leukemic and healthy hematopoietic cells. Expression of ADGRE2 appears to be relatively homogeneous across different AML subtypes, thus distinguishing as a promising target for therapy. Haubner et al. developed a novel IF-BETTER gated combinatorial CAR approach (ADCLEC.syn1) based on these two proteins: ADGRE2 is used as a CAR target and the treatment sensitivity is increased by co-engagement of a chimeric co-stimulatory receptor (CLEC12A) to expand the range of overall targetable cells. This approach exhibited high in vivo efficacy and limited off-target toxicity at clinically feasible dosing showing an increased potential for complete tumour eradication even at limiting CAR densities. This study also highlights a role for IFN-γ in mediating off-target hematotoxicity.
The CAR therapy approach described in this paper is currently being evaluated in a phase 1 clinical trial in patients with relapse or refractory AML.
8DNA hypomethylation silences anti-tumor immune genes in early prostate cancer and CTCs
Guo, H., Vuille, J. A. et al. Cell 186(13), 2765-2782.E28 (2023).
doi: doi.org/10.1016/j.cell.2023.05.028.
Summary of the findings
In addition to the established mechanism of silencing tumour suppressor genes through focal hypermethylation of CpG islands around gene promoters, long-range hypomethylation of gene-poor chromosomal regions (Partially Methylated Domains or PMDs) has been linked to silencing of resident protein-encoding genes. In their paper, Guo, Vuille, et al investigated DNA methylation features present in prostate cancer, with a focus on circulating tumour cells (CTCs). Using single-cell multiomics sequencing, combining single-cell whole-genome bisulfite sequencing with single-cell RNA-seq, the authors mapped the precise borders of PMDs that are shared across the diverse single CTCs from individual patients and across different patients. They identified 40 core PMDs, shared across all single prostate cancer cells, and traced their common origin to the early stages of tumorigenesis (Gleason stage 6) . Remarkably, a single locus encoding the entire family of CD1 genes implicated in lipid antigen presentation to NK-T cells is silenced early in tumorigenesis and restored gene expression reactivates immune cell tumour recognition. Large scale DNA hypomethylation is detectable using nanopore long-range native sequencing of CTC-enriched blood samples from patients with both localized and metastatic prostate cancer. Notably, while long range DNA hypomethylation during early tumorigenesis provides an epigenetic mechanism for bi-allelic silencing of some immune related genes, key proliferative genes that also reside within PMDs are spared, as they are surrounded by tightly demarcated islands with preserved DNA methylation.
Future impact
The specific immune-rich “CD1A-IFI16” genomic locus that is silenced by profound, early DNA hypomethylation is shared across 33 different cancer types, in addition to prostate cancer, pointing to a new, potentially targetable signaling pathway contributing to early immune surveillance of cancer. Measurements of long range DNA hypomethylation are feasible in CTC-enriched blood specimens and may enhance non-invasive detection of early malignancies.
9Immune evasion of dormant disseminated tumor cells is due to their scarcity and can be overcome by T cell immunotherapies.
Goddard, E. T., Linde, M. H. et al. Cancer Cell 42(1), 119-134.E12 (2024).
doi: doi.org/10.1016/j.ccell.2023.12.011.
Summary and graphical abstract by Alexandra Boitor, EACR Scientific Officer
Summary of the findings
A long-standing issue in combating breast cancer has been disease reoccurrence years after successful treatment of the primary tumour. Single disseminated tumour cells (DTCs), that left the primary tumour during the initial stages of tumour progression and became dormant, persisting in peripheral tissues, are believed to be at the core of breast cancer recurrence.
In this paper, the authors show that DTCs persist despite functional, antigen-specific CD8+ T cells being present simultaneously in the body and set to investigate what determines the ability of DTCs to evade immune surveillance. Through a series of in vitro and in vivo experiments, Goddard et al. were able to show that although DTCs downregulate MHC I expression as previously postulated, the reduction in MHC I expression is insufficient to fully evade identification by tumour antigen-specific T-cell receptor cells. According to this paper, the evasion of immune surveillance could be explained by the relative scarcity of the two types of cells, which reduces the likelihood of DTC-T cell interactions. Boosting the number of T cells through either T cell based vaccines or adoptive cell transfer using CAR T cells targeting CD19 or HER2, a breast cancer-relevant antigen, effectively eliminated most DTCs in mouse models. However, a small fraction of DTCs persisted in their experiments.
Findings from this study might open a new therapeutic avenue for preventing breast cancer recurrence. Future studies might look into identifying DTC-specific antigens and optimising the T Cell delivery strategies and T cell – DTC ratio for complete elimination of DTCs.
10Early-Stage Breast Cancer Detection in Breast Milk
Saura, C. et al. Cancer Discov 13 (10), 2180–2191 (2023).
doi: doi.org/10.1158/2159-8290.CD-22-1340.
Summary of the findings
Breast Cancer (BC) diagnosed during pregnancy (PrBC) or postpartum (PPBC) is independently associated with almost 30% lower 5-year survival rates than non-pregnancy-linked BC, primarily due to delays in diagnosis and presentation at an advanced stage. The limited sensitivity of standard imaging tools, coupled with morphological breast changes, contributes to the challenge of early tumor detection during pregnancy and after birth. Adjusting for clinicopathological factors does not mitigate the doubled metastatic risk of PPBC. Recognizing the urgent need for new approaches to early postpartum diagnosis, we hypothesized that breast milk (BM) could serve as an excellent source of tumor genetic material, a proposition not previously demonstrated.
Therefore, we investigated the presence of circulating tumor DNA (ctDNA) in BM and plasma from women with PrBC or PPBC and a healthy cohort. Our findings indicate that ctDNA is present in 87% of BM samples using droplet digital PCR and is detectable by targeted Next-Generation Sequencing (NGS) in 71.4% of cases, recapitulating the mutational profile of the tumors. In contrast, a mere 8% of plasma samples tested positive. Notably, in two cases, BM showed positive ctDNA levels at 18 and 6 months prior to diagnosis, suggesting a potential future use of BM as a method for early PPBC detection.
Future impact
Our data demonstrates a high prevalence of ctDNA shedding in BM, paving the way for its use as a clinically useful tool for cancer screening in a targeted population. This could include germline carriers associated with BC, women with a history of BC, or those with previous chest radiation. Further research in a larger cohort is necessary to establish a required high specificity for an acceptable positive predictive value, a crucial factor for any early detection method. In a society where factors increasing the risk of BC in young women are on the rise, such as delayed age at first pregnancy or a decrease in the number of newborns per woman, there is a need to investigate novel strategies for early PPBC detection.
