Immune cell aging is associated with compromised cancer immunosurveillance and reduced efficacy of some cancer immunotherapies. The ability to reverse immune cell aging to obtain more efficient anti-tumour reactive T cells would provide obvious benefits in clinical treatment. This could be achieved by acting on key fundamental cellular processes including metabolism and autophagy, which may subsequently influence T cell differentiation and effector functions. Polyamines, which can induce autophagy, have been shown both to enhance mitochondrial activity and have a direct effect on T cells. First by improving effector functions in CD8 T cells and, second, by regulating CD4 T cell differentiation. However, the exact interconnections between autophagy, mitochondrial activity and T-cell function remain to be elucidated. Most of the data on these fundamental processes have been collected from non-human systems, but fewer clinical data are available. We herein discuss the main evidence and speculate on the eventual benefit of affecting metabolism in an aged immune system to improve immunotherapy outcome.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) refers to the presence of a hematopoietic clone with a common leukemia driver mutation without diagnosis of an underlying hematopoietic disease. The prevalence of CHIP is increasing with age and is associated with pro-inflammatory states, higher risk of cardiovascular diseases (CVD) and therapy-induced leukemia. However, these CHIP-associated risks overlap with treatment-related toxicities of breast cancer therapy, which potentially supports the integration of CHIP into treatment- and survivorship plans. However, so far no data on the feasibility and acceptance of a CHIP-based aftercare are available. The aim of this pilot trial is to evaluate the feasibility to integrate pre-treatment CHIP diagnostics into the routine care of older breast cancer patients.

Materials and Methods: 80-100 patients with limited stage breast cancer aged ≥ 60 years without known hematological disease will be included. CHIP is assessed by targeted next generation sequencing from peripheral blood samples. The primary outcome measures the estimation of willingness to participate. Secondary outcome measures include evaluation of patient acceptance of the study process, potential fears in relation to CHIP-positivity, and cardiovascular risk profile of CHIP-positive versus CHIP-negative patients.

Conclusions: In case this study meets its primary endpoint, the results are used to design a larger cohort study that integrates an intensified CHIP-tailored survivorship program, in order to minimize late treatment-related toxicities and improve long-term outcomes of older breast-cancer patients.

Clinical trial registration number: German Clinical Trials Register (Deutsches Register für klinische Studien, DRKS) DRKS00031021.

Worldwide the cancer population is ageing-within a decade almost two-thirds of newly diagnosed patients will be aged 65 years and older. Despite this, the majority of oncology clinical trials continue to recruit patients who are younger and fitter than those typically encountered in clinical practice. As such, there is a lack of clinical data to guide management, particularly in those patients living with frailty and/or comorbidity. Importantly, the lack of older adults in trials also means that the subsequent translational work that underpins biomarker and therapeutic discovery may not be relevant to those we see in clinic. In this commentary, we discuss this challenge and the ways we as an Oncology community can look to address this pressing issue.

Aims: Aged individuals are significantly underrepresented in immunotherapy clinical trials for cancer. Little is known regarding the immunological and molecular dynamics that might regulate their responsiveness to immune checkpoint inhibitors (ICIs). This study aims to investigate the mechanisms affecting the response of elderly non-small cell lung cancer (NSCLC) patients to anti-PD-1 therapy.

Methods: We performed a single-cell analysis on public data from 419,107 tumor-infiltrating lymphocytes (TILs) across 11 elderly (≥ 65 years) and 5 non-elderly NSCLC patients treated with neoadjuvant anti-PD-1 therapy. The dataset, originally focused on mutation-associated neoantigen-specific T cells, was reprocessed to compare gene expression and molecular patterns associated with positive outcomes and tumor clearance between age groups.

Results: The analysis revealed that ICI responsiveness was not impaired by age, and T cell immunosenescence was observed in aged (≥ 65 years) and younger NSCLC individuals. Both elderly and young individuals produced responses with a heterogeneous molecular program associated with tumor-reactive CD8+ TILs. Specifically, T cells from elderly patients showed an enhanced expression of PDCD1 and CXCL13 (P < 0.001) in comparison to younger subjects.

Conclusion: Altogether, our findings demonstrate favorable molecular signatures in aged NSCLC individuals following anti-PD-1 treatment and suggest that the recruitment of older adults in immunotherapy clinical trials should not be dismissed solely on the grounds of age.

Increasing life expectancy globally results in predictions that one in six people will be > 65 years of age by 2050. Because the occurrence of most cancers is strongly associated with older age, a significant increase in the number of older adults with cancer is to be expected. It is likely that increased cancer in older adults can be explained both by the greater duration of exposure to external factors such as ultraviolet radiation, alcohol, smoking and pollution (hence modifiable by non-medical means) as well as intrinsic factors (such as metabolic stress and reactive oxygen species). These insults contribute to DNA damage and mutation that can lead to carcinogenesis if not counteracted by the appropriate repair mechanisms, or other protective strategies. Tissues from cancer-free individuals frequently contain mutations commonly observed in cancer, but these cells remain dormant until some endogenous or exogenous events promote carcinogenesis. In ageing individuals, less efficient surveillance and immune responses against cancer may represent one such event, as well as the chronic low level inflammation commonly accompanying ageing. Additionally, because of comorbidities, older patients are less robust and it is more likely that polypharmacy interferes with cancer treatment. Despite all this awareness of the impact of ageing, most cancer research, both clinical and preclinical, fails to fully consider age-associated differences in cancer occurrence and treatment, and there are very few journals specifically dedicated to publishing explorations of these issues in either the basic research or clinical context. Hence, the time has come to establish a new journal dedicated to taking a holistic approach to all aspects of cancer in older individuals. We are therefore now welcoming papers that may shed light on these increasingly important issues.