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NIH grant 1R01CA316597-01: Regulation of age-related chronic inflammation in cancer immunity
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Fumito Ito. Award: $666852.
Start: 2026-07-24T00:00:00.
PROJECT SUMMARY/ABSTRACT
Chronic inflammation increases with age, and is one of the hallmarks of cancer. A condition known as
“inflammaging” refers to a chronic, sterile low-grade inflammatory state characterized by elevated circulating
pro-inflammatory cytokines, and plays key roles in many age-related diseases, including cancer. However, the
sources and mechanisms driving the age-related increase in pro-inflammatory cytokines remain elusive.
Regarding this, we have found a higher frequency of myeloid cells expressing pro-inflammatory cytokines in
aged mice and healthy volunteers compared with their young counterparts. This is accompanied by
accelerated tumor progression in aged mice. These findings are consistent with a notion that using young mice
underestimates the impact of chronic inflammation in cancer, thereby limiting the evaluation of novel treatment
modalities on anti-tumor immune responses in elderly patients. Using aged mice, we have identified a thymic
hormone that reduces age-related pro-inflammatory cytokine production from myeloid cells, which is
associated with increased intratumoral IFN-γ-expressing T cells, improved tumor control and survival, and
enhanced sensitivity to anti-PD-1/PD-L1 therapy. Compelling evidence suggests a novel role of the thymus in
inflammaging; however, how this thymic protein regulates age-related chronic inflammation remains unclear.
The effects of decreased pro-inflammatory cytokines on the immunosuppressive tumor microenvironment are
incompletely understood. In addition, the consequences of mitigating age-related chronic inflammation on
cancer metastasis remain unknown. In this proposal we will elucidate the mechanisms underlying the
regulation of age-related pro-inflammatory cytokines using mouse and human myeloid cells in vitro and in vivo
(Aim 1). Additionally, we will define the role of this thymic protein in mitigating immunosuppression within the
aged tumor microenvironment using multiple syngeneic orthotopic mouse models of breast cancer and
melanoma that are insensitive to anti-PD-1/PD-L1 therapy (Aim 2). Finally, in Aim 3, we will determine its
impact on the development and progression of metastatic tumors, as well as its potential synergistic anti-tumor
efficacy with anti-PD-1/PD-L1 therapy using preclinical models of spontaneous metastasis. Collectively, these
studies will address gaps in our knowledge on the role of a thymic hormone in cancer immunology and
immunotherapy, yield mechanistic insights into how the thymus regulates age-related chronic inflammation,
and provide proof-of-concept that mitigating increased pro-inflammatory state is a viable strategy to enhance
the efficacy of immunotherapy in elderly cancer patients.
Justifications for the use of animals: Mice will be used as a model system for our studies that will parallel
prospective studies in aged patients with cancer that are on treatment with immune checkpoint inhibitor (ICI)
therapy under the approved IACUC protocol. The use of mice is necessary to understand inflammaging and
the mechanism of resistance to ICI therapy for aged patients with cancer.document fetched 2026-08-02 08:24