Aged Microenvironment Research Articles

Comprehensive single-cell aging atlas of healthy mammary tissues reveals shared epigenomic and transcriptomic signatures of aging and cancer.

Aging is the greatest risk factor for breast cancer; however, how age-related cellular and molecular events impact cancer initiation is unknown. In this study, we investigated how aging rewires transcriptomic and epigenomic programs of mouse mammary glands at single-cell resolution, yielding a comprehensive resource for aging and cancer biology. Aged epithelial cells exhibit epigenetic and transcriptional changes in metabolic, pro-inflammatory and cancer-associated genes. Aged stromal cells downregulate fibroblast marker genes and upregulate markers of senescence and cancer-associated fibroblasts. Among immune cells, distinct T cell subsets (Gzmk+, memory CD4+, γδ) and M2-like macrophages expand with age. Spatial transcriptomics reveals co-localization of aged immune and epithelial cells in situ. Lastly, we found transcriptional signatures of aging mammary cells in human breast tumors, suggesting possible links between aging and cancer. Together, these data uncover that epithelial, immune and stromal cells shift in proportions and cell identity, potentially impacting cell plasticity, aged microenvironment and neoplasia risk.

Reconstructing the Stem Leydig Cell Niche via the Testicular Extracellular Matrix for the Treatment of Testicular Leydig Cell Dysfunction

AbstractTherapies involving the use of stem Leydig cells (SLCs), as testicular mesenchymal stromal cells, have shown great promise in the treatment of Leydig cell (LC) dysfunction in aging males. However, the outcomes of these therapies are not satisfactory. In this study, it is demonstrated that the aging microenvironment of the testicular interstitium impairs the function of SLCs, leading to poor regeneration of LCs and, consequently, inefficient functional restoration. The study develops a decellularized testicular extracellular matrix (dTECM) hydrogel from young pigs and evaluates its safety and feasibility as a supportive niche for the expansion and differentiation of SLCs. dTECM hydrogel facilitates the steroidogenic differentiation of SLCs into LCs, the primary producers of testosterone. The combination of SLCs with a dTECM hydrogel leads to a significant and sustained increase in testosterone levels, which promotes the restoration of spermatogenesis and fertility in an LC‐deficient and aged mouse model. Mechanistically, collagen 1 within the dTECM is identified as a key factor contributing to these effects. Notably, symptoms associated with testosterone deficiency syndrome are significantly alleviated in aged mice. These findings may aid the design of therapeutic interventions for patients with testosterone deficiency in the clinic.

Abstract A011: Assessing pro-tumorigenicity of the aging microenvironment in a murine ovarian cancer model

Abstract Over 70% of high-grade serous ovarian cancer (HGSOC) patients are diagnosed after age 55 and the average patient who succumbs to HGSOC is 70 years old. Despite this, the majority of ovarian cancer studies, and cancer studies generally, utilize young mice that are more representative of human children. This approach overlooks age as a variable, despite its status as a top risk factor for cancer. Our preliminary studies reveal tumor burden and disease severity is significantly higher in aged mice compared to young animals. We have developed an epithelial cell line derived from C57BL/6 oviducts and used CRISPR-Cas9 genome editing to establish tumorigenic lines for syngeneic studies. One line harbors Trp53, Pten, and Brca2 deletions, is tumorigenic, and can be serially passaged in vitro. When injected intraperitoneally (IP) into 8-week and 56-week-old mice, equating to approximately 10- and 45-year-old humans respectively, a stark increase in tumor mass was evident in aged mice. Furthermore, the aged mice succumbed to disease at a faster rate after inoculation than the young group, where all mice succumbed to disease within 1-month of IP injection compared to some young mice surviving up to 3 months after injection. These findings, combined with epidemiologic data, suggest a metastatic driver in the aged microenvironment that facilitates worsened ovarian cancer progression. We are investigating two factors that change with age, (1) a suppressed immune system and (2) age-related changes to adipose tissue, as possible mechanisms driving this difference. Histologic analysis of tumors from each cohort showed decreased cleaved caspase-3 in aged tumors, indicating a reduction in tumor cell killing in older animals. Characterization of the pre-cancerous, tumor-naive microenvironment via flow cytometry and cytokine array have revealed that aged mice microenvironment is highly inflamed and features changes in immune populations and inflammatory states. Meanwhile, total RNA-sequencing of tumors harvested from aged and young mice showed minimal changes, but DEGs point to possible roles of fat transport and metabolism in these aged tumors, indicated by upregulated CD36 and lipoprotein lipase. Follow-up ex vivo experiments had demonstrated increased adhesion and proliferation of the previously described murine cancer cells to fat pads when cultured in vitro. When assessing tumor-naive fat depots, aged adipose tissue is comprised of significantly larger adipocytes and the omentum, a common secondary site of ovarian cancer and fatty organ, was found to have increased phospholipid content in older animals. Both findings point to a change in metabolic function in aged mice. Our preliminary findings indicate an important role of the aged microenvironment in driving enhanced diseases progression in older individuals and identifying the mechanisms behind this phenotype are critical; an improved understanding of how age affects HGSOC progression could enable the development of treatment strategies to prevent cancer cells from establishing in the peritoneum. Citation Format: Katherine A. Cummins, Ronny Drapkin. Assessing pro-tumorigenicity of the aging microenvironment in a murine ovarian cancer model [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A011.

Abstract PR003: Sex-dependent changes in the aged melanoma tumor microenvironment influence metastasis and therapeutic responses

Abstract There is documented sex disparity in cutaneous melanoma incidence and mortality, increasing disproportionately with age and in the male sex. However, the underlying mechanisms remain unclear; while biological sex differences and inherent immune response variability have been assessed in tumor cells, the role of the tumor-surrounding microenvironment, contextually in aging, has been overlooked. Dermal fibroblasts are known to have profound impact on melanoma progression. We examined if both sex-dependent and age-related changes in these fibroblasts can alter the course of melanoma tumor growth, visceral metastasis, and responses to therapy. We find that skin fibroblasts undergo age-mediated sex-differential changes in their proliferation, senescence, ROS production and stress response. We find that aged male fibroblasts drive an invasive, therapy-resistant phenotype in melanoma cells and promote metastasis in aged male mice by increasing AXL expression. Intrinsic aging promotes sex- dimorphic BMP2 secretion exclusively by aged male fibroblasts, which in turn drives the slower-cycling, highly invasive, and therapy-resistant melanoma cell phenotype, characteristic of the aged male TME. Inhibition of BMP2 activity blocks the emergence of invasive phenotype and sensitizes melanoma cells to BRAF/MEK inhibition. Our data provide an integrated view of how host factors such as advancing age and biological sex alter the tumor microenvironment and contribute to disease progression. Bridging this knowledge gap will improve patient stratification and assist in tailoring the therapy and achieve gender-equitable healthcare. Citation Format: Yash Chhabra, Ashani T. Weeraratna. Sex-dependent changes in the aged melanoma tumor microenvironment influence metastasis and therapeutic responses [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR003.

Compromised CD8+ T cell immunity in the aged brain increases severity of neurotropic coronavirus infection and postinfectious cognitive impairment.

Advanced age increases the risk of severe disease from SARS-CoV-2 infection, as well as incidence of long COVID and SARS-CoV-2 reinfection. We hypothesized that perturbations in the aged antiviral CD8+ T cell response predisposes elderly individuals to severe coronavirus infection, re-infection, and postinfectious cognitive sequelae. Using MHV-A59 as a murine model of respiratory coronavirus, we found that aging increased CNS infection and lethality to MHV infection. This was coupled with increased CD8+ T cells within the aged CNS but reduced antigen specificity. Aged animals also displayed a decreased proportion of CD103+ resident memory cells (TRM), which correlated with increased severity of secondary viral challenge. Using a reciprocal adoptive transfer paradigm, data show that not only were fewer aged CD8+ T cells retained within the adult brain post-infection, but also that adult CD8+ cells expressed lower levels of TRM marker CD103 when in the aged microenvironment. Furthermore, aged animals demonstrated spatial learning impairment following MHV infection, which worsened in both aged and adult animals following secondary viral challenge. Spatial learning impairment was accompanied by increased TUNEL positivity in hippocampal neurons, suggestive of neuronal apoptosis. Additionally, primary cell coculture showed that activated CD8+ T cells induced TUNEL positivity in neurons, independent of antigen-specificity. Altogether, these results show that non-antigen specific CD8+ T cells are recruited to the aged brain and cause broad neuronal death without establishing a TRM phenotype that confers lasting protection against a secondary infection.

Abstract IA027: Age-related stromal changes drive breast cancer tumor progression

Abstract Age is the single largest risk factor for the development of cancer, but how age impacts the molecular mechanisms that drive cancer remain poorly understood. While it is clear that age-related accumulation of cell autonomous mutations contributes to tumorigenesis, the central role age-related changes in the tumor microenvironment play in the transformation process is becoming more fully appreciated. Underscoring the importance of an aged microenvironment in cancer development are findings that senescent fibroblasts, which accumulate with age, directly stimulate preneoplastic and neoplastic cell growth and tumor progression. Investigations into how senescent fibroblasts promote tumorigenesis revealed that they express a plethora of growth factors, extracellular matrix remodeling enzymes, chemokines, and cytokines collectively referred to as the senescence associated secretory phenotype (SASP). Chemotherapy induces similar changes that can negatively impact a patient’s quality of life. We will discuss how these changes impact tumor progression and therapy-induced bone loss. Citation Format: Sheila A. Stewart. Age-related stromal changes drive breast cancer tumor progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr IA027.

Systemic and local chronic inflammation and hormone disposition promote a tumor-permissive environment for breast cancer in older women.

We uncover the unique underpinnings establishing how the systemic host environment contributes to the aged breast tumor microenvironment, characterized by high local estradiol and chronic inflammation with immune dysregulation, and show that targeting avenues of estrogen conversion and chronic inflammation work to restore anti-tumor immunity.

Engineered Age-Mimetic Breast Cancer Models Reveal Differential Drug Responses in Young and Aged Microenvironments.

Aging is one of the most significant risk factors for breast cancer. With the growing interests in the alterations of the aging breast tissue microenvironment, it has been identified that aging is related to tumorigenesis, invasion, and drug resistance. However, current pre-clinical disease models often neglect the impact of aging and sometimes result in worse clinical outcomes. In this study, we utilized aged animal-generated materials to create and validate a novel age-mimetic breast cancer model that generates an aging microenvironment for cells and alters cells towards a phenotype found in the aged environment. Furthermore, we utilized the age-mimetic models for 3D breast cancer invasion assessment and high-throughput screening of over 700 drugs in the FDA-approved drug library. We identified 36 potential effective drug targets and 34 potential drug targets with different drug responses in different age groups, demonstrating the potential of this age-mimetic breast cancer model for further in-depth breast cancer studies and drug development.

Sex dimorphism in the aged melanoma microenvironment.

Sex dimorphism in the aged melanoma microenvironment.

Regulation of Age-Related Lipid Metabolism in Ovarian Cancer.

Aging microenvironment of OC may be regulated by S100a8 and S100a9 secreted by adipocytes, preadipocytes, or neutrophils through affecting the lipid metabolism, such as FFA (18:3).

Sex-dependent effects in the aged melanoma tumor microenvironment influence invasion and resistance to targeted therapy

There is documented sex disparity in cutaneous melanoma incidence and mortality, increasing disproportionately with age and in the male sex. However, the underlying mechanisms remain unclear. While biological sex differences and inherent immune response variability have been assessed in tumor cells, the role of the tumor-surrounding microenvironment, contextually in aging, has been overlooked. Here, we show that skin fibroblasts undergo age-mediated, sex-dependent changes in their proliferation, senescence, ROS levels, and stress response. We find that aged male fibroblasts selectively drive an invasive, therapy-resistant phenotype in melanoma cells and promote metastasis in aged male mice by increasing AXL expression. Intrinsic aging in male fibroblasts mediated by EZH2 decline increases BMP2 secretion, which in turn drives the slower-cycling, highly invasive, and therapy-resistant melanoma cell phenotype, characteristic of the aged male TME. Inhibition of BMP2 activity blocks the emergence of invasive phenotypes and sensitizes melanoma cells to BRAF/MEK inhibition.

Age-Related Increases in IGFBP2 Increase Melanoma Cell Invasion and Lipid Synthesis.

The aged microenvironment drives metastasis in melanoma cells. This study reports that IGFBP2 secretion by aged fibroblasts induces lipid accumulation in melanoma cells, driving an increase in tumor invasiveness. Neutralizing IGFBP2 decreases melanoma tumor growth and metastasis.

Chronic TNF in the aging microenvironment exacerbates Tet2 loss-of-function myeloid expansion

AbstractSomatic mutations in the TET2 gene occur more frequently with age, imparting an intrinsic hematopoietic stem cells (HSCs) advantage and contributing to a phenomenon termed clonal hematopoiesis of indeterminate potential (CHIP). Individuals with TET2-mutant CHIP have a higher risk of developing myeloid neoplasms and other aging-related conditions. Despite its role in unhealthy aging, the extrinsic mechanisms driving TET2-mutant CHIP clonal expansion remain unclear. We previously showed an environment containing tumor necrosis factor (TNF) favors TET2-mutant HSC expansion in vitro. We therefore postulated that age-related increases in TNF also provide an advantage to HSCs with TET2 mutations in vivo. To test this hypothesis, we generated mixed bone marrow chimeric mice of old wild-type (WT) and TNF–/– genotypes reconstituted with WT CD45.1+ and Tet2–/– CD45.2+ HSCs. We show that age-associated increases in TNF dramatically increased the expansion of Tet2–/– cells in old WT recipient mice, with strong skewing toward the myeloid lineage. This aberrant myelomonocytic advantage was mitigated in old TNF–/– recipient mice, suggesting that TNF signaling is essential for the expansion Tet2-mutant myeloid clones. Examination of human patients with rheumatoid arthritis with clonal hematopoiesis revealed that hematopoietic cells carrying certain mutations, including in TET2, may be sensitive to reduced TNF bioactivity following blockade with adalimumab. This suggests that targeting TNF may reduce the burden of some forms of CHIP. To our knowledge, this is the first evidence to demonstrate that TNF has a causal role in driving TET2-mutant CHIP in vivo. These findings highlight TNF as a candidate therapeutic target to control TET2-mutant CHIP.

The aged tumor microenvironment limits T cell control of cancer.

The etiology and effect of age-related immune dysfunction in cancer is not completely understood. Here we show that limited priming of CD8+ T cells in the aged tumor microenvironment (TME) outweighs cell-intrinsic defects in limiting tumor control. Increased tumor growth in aging is associated with reduced CD8+ T cell infiltration and function. Transfer of T cells from young mice does not restore tumor control in aged mice owing to rapid induction of T cell dysfunction. Cell-extrinsic signals in the aged TME drive a tumor-infiltrating age-associated dysfunctional (TTAD) cell state that is functionally, transcriptionally and epigenetically distinct from canonical T cell exhaustion. Altered natural killer cell-dendritic cell-CD8+ T cell cross-talk in aged tumors impairs T cell priming by conventional type 1 dendritic cells and promotes TTAD cell formation. Aged mice are thereby unable to benefit from therapeutic tumor vaccination. Critically, myeloid-targeted therapy to reinvigorate conventional type 1 dendritic cells can improve tumor control and restore CD8+ T cell immunity in aging.

Non-pituitary growth hormone enables colon cell senescence evasion.

DNA damage-induced senescence is initially sustained by p53. Senescent cells produce a senescence-associated secretory phenotype (SASP) that impacts the aging microenvironment, often promoting cell transformation. Employing normal non-tumorous human colon cells (hNCC) derived from surgical biopsies and three-dimensional human intestinal organoids, we show that local non-pituitary growth hormone (npGH) induced in senescent cells is a SASP component acting to suppress p53. npGH autocrine/paracrine suppression of p53 results in senescence evasion and cell-cycle reentry, as evidenced by increased Ki67 and BrdU incorporation. Post-senescent cells exhibit activated epithelial-to-mesenchymal transition (EMT), and increased cell motility. Nu/J mice harboring GH-secreting HCT116 xenografts with resultant high GH levels and injected intrasplenic with post-senescent hNCC developed fourfold more metastases than did mice harboring control xenografts, suggesting that paracrine npGH enables post-senescent cell transformation. By contrast, senescent cells with suppressed npGH exhibit downregulated Ki67 and decreased soft agar colony formation. Mechanisms underlying these observations include npGH induction by the SASP chemokine CXCL1, which attracts immune effectors to eliminate senescent cells; GH, in turn, suppresses CXCL1, likely by inhibiting phospho-NFκB, resulting in SASP cytokine downregulation. Consistent with these findings, GH-receptor knockout mice exhibited increased colon phospho-NFκB and CXCL1, while GH excess decreased colon CXCL1. The results elucidate mechanisms for local hormonal regulation of microenvironmental changes in DNA-damaged non-tumorous epithelial cells and portray a heretofore unappreciated GH action favoring age-associated epithelial cell transformation.

3D bioprinted aged human post-infarct myocardium tissue model.

Fibrotic tissue formed after myocardial infarction (MI) can be as detrimental as MI itself. However, current in vitro cardiac fibrosis models fail to recapitulate the complexities of post-MI tissue. Moreover, although MI and subsequent fibrosis is most prominent in the aged population, the field suffers from inadequate aged tissue models. Herein, an aged human post-MI tissue model, representing the native microenvironment weeks after initial infarction, is engineered using three-dimensional bioprinting via creation of individual bioinks to specifically mimic three distinct regions: remote, border, and scar. The aged post-MI tissue model is engineered through combination of gelatin methacryloyl, methacrylated hyaluronic acid, aged type I collagen, and photoinitiator at variable concentrations with different cell types, including aged human induced pluripotent stem cell-derived cardiomyocytes, endothelial cells, cardiac fibroblasts, and cardiac myofibroblasts, by introducing a methodology which utilizes three printheads of the bioprinter to model aged myocardium. Then, using cell-specific proteins, the cell types that comprised each region are confirmed using immunofluorescence. Next, the beating characteristics are analyzed. Finally, the engineered aged post-MI tissue model is used as a benchtop platform to assess the therapeutic effects of stem cell-derived extracellular vesicles on the scar region. As a result, high viability (>74%) was observedin each region of the printed model. Constructs demonstrated functional behavior, exhibiting a beating velocity of 6.7 μm/s and a frequency of 0.3 Hz. Finally, the effectiveness of hiPSC-EV and MSC-EV treatment was assessed. While hiPSC-EV treatment showed no significant changes, MSC-EV treatment notably increased cardiomyocyte beating velocity, frequency, and confluency, suggesting a regenerative potential. In conclusion, we envision that our approach of modeling post-MI aged myocardium utilizing three printheads of the bioprinter may be utilized for various applications in aged cardiac microenvironment modeling and testing novel therapeutics.

Abstract 5541: The unique metabolite landscape of the aged microenvironment dictates melanoma migratory and invasive capacity

Abstract Metastatic burden and organ failure are the root causes of mortality in patients with advanced melanoma; however, little is known of the metabolic drivers that enable organ colonization and the formation of overt metastases. Recent studies have drawn attention to the importance of metabolism in the survival and colonization of cancer cells. In melanoma, there have been studies focusing on the invasive capabilities of cells; however, not much is known regarding metabolic plasticity in melanoma migratory, invasive and ultimately metastatic capabilities.We have previously shown changes in the lipid landscape of the aged microenvironment promotes melanoma resistance to targeted therapy. Here, we find a distinct metabolite landscape in the aged microenvironment elevates melanoma metastatic capacity. We utilized a panel of well characterized melanoma models and tested their invasiveness and motility under different metabolite levels modeled after the aged microenvironment. Transcriptomic and proteomic analysis identifies distinct signatures that explain the migratory and invasive differences in cells cultured in varying metabolic environments. We hypothesize that different nutrient availabilities melanoma cells are exposed to during the metastatic phase affect the migratory and invasive capacity of the cell. We tested this by performing 3D migration assays, organoids and transwell assays of cells grown in media with varying nutrient levels. Further analysis is currently underway to better understand the mechanisms in which these metabolic differences facilitate cell migration, invasion and eventually colonization. This work has important implications for our understanding of the metabolic determinants of melanoma migration and metastatic colonization, and we hypothesize restraining tumor metabolic plasticity is vital to prevent and treat metastases in melanoma. Citation Format: Gretchen Marie Alicea, Payal Patel, Meihan Wei, Vito Rebecca, Denis Wirtz. The unique metabolite landscape of the aged microenvironment dictates melanoma migratory and invasive capacity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5541.

Abstract 3921: The aged tumor microenvironment limits CD8+ T cell control of cancer

Abstract Aging is associated with progressive loss of immune function, which parallels the rise in cancer incidence. The etiology and impact of age-related CD8+ T cell dysfunction in cancer remain poorly understood. Here, we demonstrate that increased tumor growth in aged hosts is associated with reduced CD8+ T cell infiltration and function. The transfer of young antigen-specific CD8+ T cells fails to restore tumor control in aged hosts due to the rapid induction of CD8+ T cell dysfunction. The aged tumor microenvironment drives a novel age-associated dysfunctional state (TADys) that is functionally, transcriptionally, and epigenetically distinct from canonical CD8+ T cell exhaustion. Overall, this study focuses on understanding the cell-intrinsic and -extrinsic effects on CD8+ T cell immunity in aging and explores a proper strategy to improve CD8+ T cell control of cancer. Citation Format: Alex C.Y. Chen, Sneha Jaiswal, Daniela Martinez, Cansu Yerinde, Keely Ji, Velita Miranda, Megan E. Fung, Sarah A. Weiss, Maria Zschummel, Kazuhiro Taguchi, Christopher S. Garris, Thorsten R. Mempel, Debattama R. Sen. The aged tumor microenvironment limits CD8+ T cell control of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3921.

Abstract 5513: Sexual differences in the aged melanoma tumor microenvironment dictates metastasis and therapeutic responses

Abstract There is documented sex disparity in cutaneous melanoma incidence and mortality, increasing disproportionately with age and in the male sex. However, the underlying mechanisms remain unclear; while biological sex differences and inherent immune response variability have been assessed in tumor cells, the role of the microenvironment surrounding the tumor, contextually in aging, has been overlooked. We find that skin fibroblasts undergo age-mediated changes in their proliferation, senescence, ROS levels and stress response that vary with sex. We find that aged male fibroblasts selectively drive an invasive and slow-cycling phenotype in melanoma cells in vitro by increasing AXL expression. This is also evident in syngeneic mouse models where metastasis is increased in aged male mice. Mechanistically, intrinsic aging in male fibroblasts coupled with elevated ROS promotes EZH2 decline thereby increasing BMP2 secretion, which in turn drives the slower-cycling, highly invasive, and therapy-resistant melanoma cell phenotype, characteristic of the aged male TME. Inhibition of BMP2 activity blocks the emergence of the invasive phenotype and sensitizes melanoma cells to BRAF/MEK inhibition. Our data provides an integrated view of how age and sex of the host contributes to melanoma progression and therapy responses. Bridging this knowledge gap will improve patient stratification and assist in tailoring the therapy to the individual. Citation Format: Yash Chhabra, Mitchell Fane, Sneha Pramod, Laura Hueser, Daniel Zabransky, Vania Wang, Edwin Kumah, Alexis Carey, Elizabeth Harper, Murilo Ramos Rocha, Ashani Weeraratna. Sexual differences in the aged melanoma tumor microenvironment dictates metastasis and therapeutic responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5513.

Abstract 1407: Investigating the effect of an aged liver microenvironment on immune surveillance and predisposition to cancer​

Abstract The incidence of liver cancer is increasing and there is an urgent need for new therapies and preventative strategies. Age is a major risk factor for liver cancer, the reasons for which are not well defined. One of the hallmarks of aging is immune dysfunction which affects liver homeostasis potentially making it prone to cancer. To understand the role of immune dysfunction in aging liver, we analyzed immune cells from young and old livers. As is reported before, in aged livers we observed an increase in CD101+PD1+CD8+ T cell population as well as an increase in an IFNγ+TNFα+ population suggesting an increase in T cell response in an aging liver. We next sought to understand the cause of T cell exhaustion in aged livers. Cell cluster analysis of the young (4-month-old) and old (22 month old) livers by scRNA seq revealed a cell population unique to the aged livers, showing increased expression of immune checkpoint ligands as well as tumor-initiating cell markers. We validated this data by flow cytometry. We next functionally probed the immune environment of aged liver, by testing the effect of cognate antigen expression in young and old hepatocytes on adoptively transferred activated P14 CD8+ T cells isolated from a young P14 mouse. Analysis of the ex vivo activated P14 CD8+ T cells from young and old antigen-expressing livers by flow cytometry and scRNA sequencing revealed increased exhaustion and cytokine-deficiency in old mice as compared to the young mice. This study explores the age-associated alterations in the immune cells in the liver, aiming to alter liver-resident immune cells and their metabolic states in a way that promotes anti-tumor immunity in an aging liver. Citation Format: Armin Aabish Gandhi, Filipe Araujo Hoffmann, Michael LaPorte II, Aaron Havas, Adarsh Rajesh, Andrew Davis, Marcos G. Teneche, Jessica Proulx, Susan Kaech, Peter D. Adams. Investigating the effect of an aged liver microenvironment on immune surveillance and predisposition to cancer​ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1407.