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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- Cancer cell autophagy, reprogrammed macrophages, and remodeled vasculature in glioblastoma triggers tumor immunity
- A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation
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Breast tumor microenvironment structures are associated with genomic features and clinical outcome
- Chronic exposure to carbon black ultrafine particles reprograms macrophage metabolism and accelerates lung cancer
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Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer
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Deciphering the immunopeptidome in vivo reveals new tumour antigens
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RASA2 ablation in T cells boosts antigen sensitivity and long-term function
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Sensitisation of cancer cells to radiotherapy by serine and glycine starvation
1Cancer cell autophagy, reprogrammed macrophages, and remodeled vasculature in glioblastoma triggers tumor immunity

Chryplewicz, A. et al. Cancer Cell. 40(10):1111-1127. (2022).
doi: 10.1016/j.ccell.2022.08.014.
Summary of the findings
Future impact
This investigation has revealed a provocative new therapeutic approach involving clinically approved drugs that unleashed a potent anti-tumoral immune response in a tumor type that is otherwise refractory to immune intervention. Given the transient response and the dismal prognosis of GBM patients on standard-of-care therapies, these findings motivate consideration of proof-of-concept clinical trials aimed to evaluate the translational potential of TCAs combined with VEGF pathway inhibitors and immune checkpoint blockade. Notably, this study has motivated the Mark Foundation to support a clinical trial in GBM patients progressing on first-line treatment.
2A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation
Yanchus, C., Drucker, K., L. et al. Science. 378(6615):68-78. (2022).
doi: 10.1126/science.abj2890.
Summary of the findings
“It’s an amazing story how one nucleotide change in the non-coding genome can dramatically alter cancer susceptibility in large number of patients. ” EACR Board
Genome-wide association studies have found multiple single-nucleotide polymorphisms (SNP) that are associated with glioma, but the mechanism of action for nearly all the polymorphisms has long been unknown. Prior studies had found the SNP rs55705857 was associated with risk of developing IDH-mutant gliomas; this SNP was located in a region of the genome that has been of interest in many different cancer types. Fine-mapping of the locus narrowed the region of interest and again confirmed that the rs55705857-G risk allele is the likely causative allele. Histone chromatin immunoprecipitation showed that the rs55705857 locus encompasses a brain -specific enhancer and demonstrated increased enhancer activity in human IDH-mutant versus IDH-wildtype glioma. Reporter assays in mouse embryos further observed increased activity of the enhancer containing the rs55705857-G risk allele.

Future impact
Many different loci for genetic predisposition have been found for IDH-mutant glioma, most of which are located in non-coding regions of the genome. This study demonstrates that the function of these loci can be evaluated by current technology. The study also suggests that the rs55705857 region may have future cancer therapeutic and preventative relevance for IDH-mutant gliomas.
3Breast tumor microenvironment structures are associated with genomic features and clinical outcome
Danenberg, E. et al. Nature Genetics. 54: 660–669 (2022).
doi: 10.1038/s41588-022-01041-y.
Summary of the findings
The functions of the tumour microenvironment (TME) are orchestrated by precise spatial organisation of specialised cells, yet we know very little about the multicellular structures that form within the TME. We systematically mapped TME structures in situ using imaging mass cytometry and multi-tiered spatial analysis of 693 breast tumours linked to genomic and clinical data. We borrowed methods used in the analysis of social networks to discover recurrent spatially conserved orientations of immune and stromal cells (TME structures). We identified 10 recurrent TME structures that varied by vascular content, stromal quiescence versus activation, and leukocyte composition. These TME structures had distinct enrichment patterns among breast cancer subtypes, and some were associated with genomic profiles indicative of immune escape. Regulatory and dysfunctional T cells co-occurred in large ‘suppressed expansion’ structures. These structures were characterized by high cellular diversity, proliferating cells, and enrichment for BRCA1 and CASP8 mutations, and predicted poor outcome in ER-positive disease. The landscape of multicellular structures revealed here links conserved spatial organisation to local TME function and holds potential for better patient stratification. All data have been deposited in the public domain, and should serve as a resource for other studies of the multicellular organisation of breast cancer.

4A covalent inhibitor of K-Ras(G12C) induces MHC class I presentation of haptenated peptide neoepitopes targetable by immunotherapy
Zhang, Z., Rohweder, P., J. et al. Cancer Cell. 40(9): 1060-1069. (2022).
doi: 10.1016/j.ccell.2022.07.005.
Summary of the findings

The development of novel immunotherapies is limited by the availability of tumor-specific antigens. Mutant oncoproteins are amongst the most attractive targets as they are inherently tumor-specific, but these proteins are often intracellular and not accessible to protein- or cell-based therapies. Nature solves this problem with the native antigen presentation pathway, which uses MHC I molecules to bring intracellular protein fragments to the cell surface for T cell recognition. Immunotherapies targeting oncoprotein-derived MHC I complexes have emerged as a promising new avenue for expanding the scope of targetable tumor-specific antigens. In this Cancer Cell paper, Zhang et al. expand further upon this approach by demonstrating that KRas G12C proteins treated with covalent inhibitors can be processed through the antigen presentation pathway, resulting in the presentation of MHC I complexes containing inhibitor-modified KRas G12 peptides. These inhibitor-modified MHC I complexes represent a new class of tumor-specific antigens, requiring both a mutant oncoprotein (KRas G12C) and the presence of a covalent inhibitor for generation of the target antigen. The authors were able to identify antibodies specific to inhibitor-modified MHC I complexes containing the preclinical KRas G12C inhibitor ARS1620 and the FDA-approved inhibitor Sotorasib. Using a bispecific T-cell engager derived from an inhibitor-specific antibody, the authors show that these MHC I complexes can be targeted for immunotherapy, offering superior efficacy to treatment with the covalent inhibitor alone. The authors demonstrate that covalent inhibitors can serve to potentiate immunotherapy, offering the potential for synergistic approaches leveraging the distinct modalities of both small molecule inhibitors and protein-based immunotherapies.
Future impact
The expansion of targetable antigens is critical for the continued development of immunotherapies. With two covalent KRas G12C inhibitors now approved by the FDA and multiple in clinical trials, immunotherapies targeting neoantigens derived from these inhibitors have the potential to improve clinical efficacy via combination therapies and could be used to reclaim clinical efficacy in the case of acquired or innate resistance to the inhibitor monotherapy. With many other covalent inhibitors currently in development or already in use clinically, this novel class of neoantigen could become an important source of targets for future immunotherapies.
5Chronic exposure to carbon black ultrafine particles reprograms macrophage metabolism and accelerates lung cancer
Chang, C-Y. et al. Science Advances. 8(46). (2022).
doi: 10.1126/sciadv.abq0615.
Summary of the findings

Future impact
Cigarette smoking remains the number one cause of lung cancer worldwide. However, exposure to industrial and environmental air pollution impacts a broader range of the population at risk. This study shows that small airborne particles, nCB, can promote immunosuppression in the lung, demonstrating the importance of environmental pollutants in cancer development. The newly discovered immunometabolic pathways identified in this study play a key role in lung cancer development and progression. Harnessing the molecular mechanisms critical in changing the immune environment in the lungs could be used to provide new treatment options for preventing and or treating lung cancer.
6Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer
Herberts, C., Annala, M., Sipola, J. et al. Nature. 608: 199-208. (2022).
doi: 10.1038/s41586-022-04975-9.
Summary of the findings

Future impact
This expansion of liquid biopsy technology will inform the next generation of comprehensive clinical ctDNA biomarker tests, helping clinicians choose treatments better tailored to their patients’ unique cancer biology. Beyond impacting patient care, the author’s research proposes ctDNA testing as a novel research modality to accelerate the discovery of treatment resistance mechanisms to common cancer drugs. This methodology can be applied to other cancer types to reveal new biological insight (e.g. how do tumours metastasize; how do tumours evade therapy?) but also help design new cancer therapies that more effectively target resistant disease.
7Deciphering the immunopeptidome in vivo reveals new tumour antigens
Jaeger, A., M. et al. Nature. 607: 149-155. (2022).
doi: 10.1038/s41586-022-04839-2.
Summary of the findings
“They designed a methodology that allows precise isolation of tissue-specific pMHC complexes. This enables the identification of cancer-specific epitopes, and a comparison between the tumour and normal immunopeptidoms.” EACR Board
Despite great advances in the cancer immunotherapy field, the impact of the microenvironment, tissue-specific stimuli, and heterogeneity of the tumour tissue on the immunopeptidome is still unclear. To address this issue, Jaeger et al. have developed a genetic tool that allows for the precise isolation of MHC-I peptides in vivo only from the cells of interest. This system consists of genetically engineered mouse models that express Cre-inducible Strep tags onto MHC-I peptides. When applied to mouse models of lung adenocarcinoma, this system led to the identification of a set of tumour-specific peptides that were missed by traditional antibody approaches. The authors go on to show a progressive divergence of the tumour immunopeptidome from normal tissue as the disease progresses and highlighted the heterogeneity of antigen presentation across cancer cell states. The authors also noted that mRNA expression and differential translation efficiency cannot be solely responsible for the unique presentation of individual peptides in lung adenocarcinoma and suggest that the Cre-strep model they developed could identify changes to the immunopeptidome inferred through post-translational mechanisms. Finally, by using this system the authors identified a number of putative non-mutated tumour-specific antigens and putative tumour-associated antigens and demonstrate the immunogenic potential of two such peptides that would have likely been missed by other more traditional methods.

Future impact
As shown in this paper, this new tool has the ability to identify peptides derived as a result of physical cues from the microenvironment and could as such be used to identify and evaluate promising peptides for the development of new cancer immunotherapies. Moreover, the authors of the paper envision that the use of this model could lead to the development of a high-resolution in vivo immunopeptidome atlas by adapting the model to investigate the immunopeptidome in other tissues and cancer types.
Summary, Future impacts and Graphical abstract by Alexandra Boitor.
8Lung fibroblasts facilitate pre-metastatic niche formation by remodeling the local immune microenvironment
Gong, Z., Li, Q. et al. Immunity. 55(8): 1483-1500. (2022).
doi: 10.1016/j.immuni.2022.07.001.
Summary of the findings

Metastatic disease remains the leading cause of cancer-related death, and the lung is one of the most common organs to which solid tumors metastasize. It has been widely acknowledged that the formation of an immunosuppressive lung microenvironment is critical for disseminated tumor cells (DTCs) from a primary tumor to develop successful metastatic lung colonization. However, little is known about how the local lung stroma contributes to the formation of such an immunosuppressive niche. In this work, a unqiue lung stromal regulatory program was identified to play a decisive role in establishing a robust immunosuppressive lung milieu. Different types of bone marrow-derived myeloid cells, when infiltrating the lung, were reprogrammed by lung-resident cyclooxygenase 2 (COX-2)-expressing adventitial fibroblasts (AdvF) to become immunosuppressive and/or dysfunctional. This lung stromal program exists at the steady state, and is reinforced by tumor-bearing conditions, especially tumor-associated inflammation. Through this driver role, lung fibroblasts elicit formation of a receptive niche that fosters DTC colonization via evasion of lung-resident anti-tumor immunity. Genetic ablation or pharmacological targeting of the lung fibroblast signaling molecules largely restored local anti-tumor immunity, mitigated lung metastasis, and improved the therapeutic efficacy of immunotherapeutics in treating lung metastasis.
Future impact
Understanding how metastatic tumor cells colonize distant organs by evasion of the local anti-tumor immunity is an essential step towards developing effective therapeutics to treat metastatic disease. This study deciphered a lung-intrinsic immunosuppressive program instigated by Ptgs2high tissue-resident fibroblasts, which is hijacked by breast tumor cells for their metastasis. As lung fibroblasts actively remodel the immune landscape in the lung, targeting fibroblast-associated signaling molecules would be a promising approach for lung metastasis treatments, particularly in combination with immunotherapeutics that are already in wide use. The findings also offer insights for studying stromal-immune cell interactions in other metastatic organs.
9RASA2 ablation in T cells boosts antigen sensitivity and long-term function
Carnevale, J., Shifrut, E. et al. Nature. 609: 174–182. (2022).
doi: 10.1038/s41586-022-05126-w.
Summary of the findings
We previously developed a strategy to enable pooled CRISPR screening in primary human T cells, enabling genome-wide queries for genes regulating key T cell functions. In this paper by Carnevale and Shifrut et al., we adapt this screening platform to model different factors that suppress T cells in the tumor microenvironment in order to identify gene targets that confer resistance to these forms of suppression. We identify RASA2, a RasGAP never before studied in immune cells, as a target gene shared across our screens. We show that RASA2 is a negative regulator of TCR stimulation and activation. RASA2 deletion increases T cell sensitivity to antigen and enhances TCR signaling responses. We find RASA2 is upregulated in the setting of chronic antigen stimulation, and that knocking out RASA2 enhances persistent effector function in the setting of repeated tumor cell exposures. RASA2 deletion alters the metabolic fitness in T cells, increasing both the spare respiratory capacity and glycolytic activity. In preclinical models both liquid and solid tumors, deletion of RASA2 in TCR-T and CAR-T cells increases tumor burden control and survival. We identify RASA2 as a new target to engineer more potent and persistent T cell therapies for cancer treatment.

Future impact
We have demonstrated the power of unbiased CRISPR screening to discover new biology in primary T cells that has direct translational implications. We identified a number of genes that regulate T cell activation and proliferation in the context of different suppressive factors that can be found in the tumor microenvironment. We show that targeted deletion of one of these genes, RASA2, generates engineered T cells with remarkable persistence in tumor killing. RASA2 is an exciting new gene target that can be manipulated in T cell therapies and holds promise for treating both liquid and solid tumors.
10Sensitisation of cancer cells to radiotherapy by serine and glycine starvation
Falcone, M., Uribe, A., H. et al. Br J Cancer. 127: 1773–1786. (2022).
doi: 0.1038/s41416-022-01965-6.
Summary of the findings
About 50% of all cancer patients are treated with radiotherapy at some stage of their disease. This directly damages DNA and generates radiation-induced reactive oxygen species (ROS), causing further oxidative damage. Boosting both of these processes establishes the backbone of radiotherapy resistance. However, the metabolic mechanisms have been poorly characterised.
The non-essential amino acid Serine and Glycine (SG) are the major contributors of carbon and nitrogen units for nucleotide and glutathione synthesis – the main cellular antioxidant. Dietary limitation of SG in several cancer models has shown exceptional results, especially in combination with standard therapies. Thus, we sought to investigate the impact of SG restriction on radiotherapy.
We show a dramatic dose and time-dependent metabolic response to radiation in various cancers. In addition to predicted metabolic rewirings (e.g. nucleotides and glutathione synthesis), we unexpectedly found a consistent increase of Krebs cycle intermediates. We demonstrated that SG starvation could prevent this upregulation, making this pathway a significant component in cancer cells’ metabolic response to radiotherapy. Our results corroborate prior works demonstrating the sensitising effect of mitochondrial inhibition. Altogether we highlight the potential of combining dietary nutrient modulation with standard cancer therapy as a means of sensitisation.

Future impact
This study explored the metabolic response to radiotherapy. We suggest combining dietary limitations of the non-essential amino acid serine and glycine SG as a potentially effective strategy to sensitise a range of common cancers to radiotherapy. Amino acid-restricted diets are now beginning to enter clinical trials making this study highly relevant. Establishing the pre-clinical efficacy of sensitising adjuvants in multiple tumour types is the answer to a pressing clinical need.
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