Exercise-induced engagement of the IL-15/IL-15RÎ± axis promotes anti-tumor immunity in pancreatic cancer
Aerobic exercise is associated with decreased cancer incidence and cancer-associated mortality. However, little is known about the effects of exercise on pancreatic ductal adenocarcinoma (PDA), a disease for which current therapeutic options are limited. Herein, we show that aerobic exercise reduces PDA tumor growth, by modulating systemic and intra-tumoral immunity. Mechanistically, exercise promotes immune mobilization and accumulation of tumor-infiltrating IL15RÎ±+ CD8 TÂ cells, which are responsible for the tumor-protective effects. In clinical samples, an exercise-dependent increase of intra-tumoral CD8 T cells is also observed. Underscoring the translational potential of the interleukin (IL)-15/IL-15RÎ± axis, IL-15 super-agonist (NIZ985) treatment attenuates tumor growth, prolongs survival, and enhances sensitivity to chemotherapy. Finally, exercise or NIZ985 both sensitize pancreatic tumors to Î±PD-1, with improved anti-tumor and survival benefits. Collectively, our findings highlight the therapeutic potential of an exercise-oncology axis and identify IL-15 activation as a promising treatment strategy for this deadly disease.
Metabolic reprogramming of tumor-associated macrophages by collagen turnover promotes fibrosis in pancreatic cancer
SignificanceThe highly desmoplastic and immunosuppressive microenvironment of pancreatic tumors is a major determinant of the aggressive nature and therapeutic resistance of pancreatic cancer. Therefore, improving our understanding of the mechanisms that regulate the composition and function of the pancreatic tumor microenvironment is critical for the design of intervention strategies for this devastating malignancy. This study identifies a modality for the reprogramming of tumor-associated macrophages involving collagen scavenging followed by a metabolic switch toward a profibrotic paracrine phenotype. These findings establish a molecular framework for the elucidation of regulatory processes that could be harnessed to mitigate the stroma-dependent protumorigenic effects in pancreatic cancer.
A phase 1b study evaluating IL-1beta and PD-1 targeting with chemotherapy in metastatic pancreatic cancer (PanCAN-SR1) [Meeting Abstract]
Background: Pancreatic ductal adenocarcinoma (PDA) is a highly lethal malignancy that is refractory to therapeutic targeting of the immune microenvironment. In preclinical work, IL-1beta was shown to be upregulated in pancreatic cancer tumors, and in mouse models, IL-1beta expression led to activation of pancreatic stellate cells and immunosuppression (Das et al 2020). We hypothesize that blockade of IL-1beta and PD-1 will result in alterations in myeloid, lymphoid, and fibroblast subsets within the pancreatic cancer microenvironment and add therapeutic benefit in combination with chemotherapy in PDA.
Method(s): We are conducting an open-label multicenter Phase Ib study evaluating a 4 drug regimen including gemcitabine and nabpaclitaxel with the addition of canakinumab (ACZ885), a high-affinity human anti-interleukin1beta (IL-1beta) monoclonal antibody (mAb), and spartalizumab (PDR001), a mAb directed against human Programmed Death-1 (PD-1). Eligible subjects have metastatic PDA without prior anticancer therapy for metastatic disease and RECIST measurable disease. The primary objective was to identify a recommended phase II/III dose of combination therapy by evaluating the incidence of dose limiting toxicities in the first 56 days (8 weeks) of dosing in at least 6 evaluable subjects utilizing a Bayesian logistic regression model. All subjects underwent baseline and on-study tissue and blood collection for extensive exploratory correlative studies. Secondary objectives including safety and tolerability of quadruple therapy and preliminary assessment of clinical activity.
Result(s): 10 subjects were enrolled between November 2020 and March 2021, and the first 6 subjects to complete 8 weeks of therapy were included in the dose confirmation analysis. There were no dose limiting toxicities and the recommended Phase II/III dose was established as; gemcitabine (1000 mg/m2 IV) on day 1,8,15; nab-paclitaxel (125 mg/m2 IV) on day 1,8,15, canakinumab (250 mg via subcutaneous injection) on day 1, spartalizumab (400 mg IV) on day 1; of each 28 day cycle. Adverse events were consistent with those seen with chemotherapy and were predominately hematologic. The majority of subjects completed the on-treatment blood and tissue collection for correlative analysis. The study is ongoing with subjects remaining on therapy and all subjects will be evaluated for efficacy.
Conclusion(s): In this Phase Ib study, we demonstrated the feasibility and safety of adding canakinumab and spartalizumab to standard of care chemotherapy in first line metastatic PDA and established the recommended Phase II/III dose. This novel 4 drug combination will be tested in a randomized Phase II/III study through the Precision Promise clinical trial network. Preliminary correlative and efficacy data will be reported
EMSY inhibits homologous recombination repair and the interferon response, promoting lung cancer immune evasion
Non-small cell lung cancers (NSCLCs) harboring KEAP1 mutations are often resistant to immunotherapy. Here, we show that KEAP1 targets EMSY for ubiquitin-mediated degradation to regulate homologous recombination repair (HRR) and anti-tumor immunity. Loss of KEAP1 in NSCLC induces stabilization of EMSY, producing a BRCAness phenotype, i.e., HRR defects and sensitivity to PARP inhibitors. Defective HRR contributes to a high tumor mutational burden that, in turn, is expected to prompt an innate immune response. Notably, EMSY accumulation suppresses the type I interferon response and impairs innate immune signaling, fostering cancer immune evasion. Activation of the type I interferon response in the tumor microenvironment using a STING agonist results in the engagement of innate and adaptive immune signaling and impairs the growth of KEAP1-mutant tumors. Our results suggest that targeting PARP and STING pathways, individually or in combination, represents a therapeutic strategy in NSCLC patients harboring alterations in KEAP1.
Exploiting cancer's drinking problem: regulation and therapeutic potential of macropinocytosis
Macropinocytosis, an evolutionarily conserved endocytic mechanism that mediates non-specific fluid-phase uptake, is potently upregulated by various oncogenic pathways. It is now well appreciated that high macropinocytic activity is a hallmark of many human tumors, which use this adaptation to scavenge extracellular nutrients for fueling cell growth. In the context of the nutrient-scarce tumor microenvironment, this process provides tumor cells with metabolic flexibility. However, dependence on this scavenging mechanism also illuminates a potential metabolic vulnerability. As such, there is a great deal of interest in understanding the molecular underpinnings of macropinocytosis. In this review, we will discuss the most recent advances in characterizing macropinocytosis: the pathways that regulate it, its contribution to the metabolic fitness of cancer cells, and its therapeutic potential.
Gain-of-function p53R172H mutation drives accumulation of neutrophils in pancreatic tumors, promoting resistance to immunotherapy
Tumor genotype can influence the immune microenvironment, which plays a critical role in cancer development and therapy resistance. However, the immune effects of gain-of-function Trp53 mutations have not been defined in pancreatic cancer. We compare the immune profiles generated by KrasG12D-mutated mouse pancreatic ductal epithelial cells (PDECs) engineered genetically to express the Trp53R172H mutation with their p53 wild-type control. KrasG12D/+;Trp53R172H/+ tumors have a distinct immune profile characterized by an influx of CD11b+Ly6G+ neutrophils and concomitant decreases in CD3+ TÂ cells, CD8+ TÂ cells, and CD4+ T helper 1 cells. Knockdown of CXCL2, a neutrophil chemokine, in the tumor epithelial compartment ofÂ CRISPR KrasG12D/+;Trp53R172H/+ PDEC tumors reverses the neutrophil phenotype. Neutrophil depletion of mice bearing CRISPR KrasG12D/+;Trp53R172H/+ tumors augments sensitivity to combined CD40 immunotherapy and chemotherapy. These data link Trp53R172H to the presence of intratumoral neutrophils in pancreatic cancer and suggest that tumor genotypes could inform selection of affected individuals for immunotherapy.
A novel target for combination immunotherapy in pancreatic cancer: IL-1Î² mediates immunosuppression in the tumour microenvironment
Immune checkpoint blockade (ICB) has demonstrated efficacy in multiple cancers, offering the potential of long-term disease control not achievable with cytotoxic or targeted therapies. However, the field has not yet achieved the crucial next stepsÂ - the expansion of the response rate and achievement of clinical efficacy in so-called "cold tumours". Mechanistic studies of tumour-type specific immunosuppressive pathways can reveal underlying biological hurdles to immunotherapy and offer new therapeutic insights. Our finding that tumour-derived IL-1Î² mediates immunosuppression in pancreatic cancer has precipitated a new clinical trial.
Integrated Systems Analysis of the Murine and Human Pancreatic Cancer Glycomes Reveals a Tumor-Promoting Role for ST6GAL1
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States. Glycans, such as carbohydrate antigen 19-9, are biomarkers of PDAC and are emerging as important modulators of cancer phenotypes. Herein, we used a systems-based approach integrating glycomic analysis of the well-established KC mouse, which models early events in transformation, and analysis of samples from human pancreatic cancer patients to identify glycans with potential roles in cancer formation. We observed both common and distinct patterns of glycosylation in pancreatic cancer across species. Common alterations included increased levels of Î±-2,3-sialic acid and Î±-2,6-sialic acid, bisecting GlcNAc and poly-N-acetyllactosamine. However, core fucose, which was increased in human PDAC, was not seen in the mouse, indicating that not all human glycomic changes are observed in the KC mouse model. In silico analysis of bulk and single-cell sequencing data identified ST6 beta-galactoside alpha-2,6-sialyltransferase 1, which underlies Î±-2,6-sialic acid, as overexpressed in human PDAC, concordant with histological data showing higher levels of this enzyme at the earliest stages. To test whether ST6 beta-galactoside alpha-2,6-sialyltransferase 1 promotes pancreatic cancer, we created a novel mouse in which a pancreas-specific genetic deletion of this enzyme overlays the KC mouse model. The analysis of our new model showed delayed cancer formation and a significant reduction in fibrosis. Our results highlight the importance of a strategic systems approach to identifying glycans whose functions can be modeled in mouse, a crucial step in the development of therapeutics targeting glycosylation in pancreatic cancer.
Î³Î´ T Cells Support Pancreatic Oncogenesis by Restraining Î±Î² T Cell Activation
Macropinocytosis as a Key Determinant of Peptidomimetic Uptake in Cancer Cells
Peptides and peptidomimetics represent the middle space between small molecules and large proteins-they retain the relatively small size and synthetic accessibility of small molecules while providing high binding specificity for biomolecular partners typically observed with proteins. During the course of our efforts to target intracellular protein-protein interactions in cancer, we observed that the cellular uptake of peptides is critically determined by the cell line-specifically, we noted that peptides show better uptake in cancer cells with enhanced macropinocytic indices. Here, we describe the results of our analysis of cellular penetration by different classes of conformationally stabilized peptides. We tested the uptake of linear peptides, peptide macrocycles, stabilized helices, Î²-hairpin peptides, and cross-linked helix dimers in 11 different cell lines. Efficient uptake of these conformationally defined constructs directly correlated with the macropinocytic activity of each cell line: high uptake of compounds was observed in cells with mutations in certain signaling pathways. Significantly, the study shows that constrained peptides follow the same uptake mechanism as proteins in macropinocytic cells, but unlike proteins, peptide mimics can be readily designed to resist denaturation and proteolytic degradation. Our findings expand the current understanding of cellular uptake in cancer cells by designed peptidomimetics and suggest that cancer cells with certain mutations are suitable mediums for the study of biological pathways with peptide leads.