Aims: The combination of CDK4/6 inhibitors and endocrine therapy (ET) is a standard first-line therapy for hormone receptor positive (HR+)/HER2- metastatic breast cancer (mBC). Preliminary data suggest that CDK4/6 inhibitors can alter the host immune function and stimulate tumor cell-directed immunity. However, clinical data are scarce, and no data exist about the impact of age and frailty on this phenomenon.

Materials and Methods: This biomarker substudy of the RibOB trial evaluated the impact of ribociclib and letrozole on circulating immune cell subsets and protein markers in older (≥ 70 years) patients with HR+/HER2- mBC. Peripheral blood mononuclear cell subtyping and analysis of plasma immune response and checkpoint markers were performed using flow cytometry at baseline and after three months of ribociclib + ET. Frailty status was assessed at baseline using G8 score.

Results: 20 patients (median age: 76 years, range: 70-87 years), 8 considered fit (G8 > 14), and 12 frail (G8 ≤ 14), were included. After three months of treatment, the immune subset composition showed significant increases in naïve B-, T-regulatory (Tregs), and CD4+ T-cells, while memory B-cells and Tregs were significantly decreased. In addition, consistent upregulation was seen in costimulatory receptors CD27 and CD28. Plasma immune checkpoint markers B7.2 (CD86) and PD-1 were significantly decreased. The immune subset profiles of fit versus frail persons showed no statistically significant difference.

Conclusion: The study shows that the combination of ribociclib and ET modulates the immune system in older patients, potentially reversing the age-related immunosenescence process by increasing naïve T-cell and B-cell populations and decreasing memory populations.

Clinical trial registration number: NCT03956654.

The global aging population is expected to experience a nofigure increase in cancer incidence, particularly among individuals aged 70 and older. At the same time, the extensive use of immune checkpoint inhibitors (ICIs) in cancer treatment raises questions about the influence of immunosenescence, the age-related decline in immune function, on treatment efficacy in older patients. Despite promising outcomes, resistance to immunotherapies and the occurrence of severe immune-related adverse events (irAEs) remain challenges. Limited research has explored the correlation between immunosenescence markers in peripheral blood and the tumour microenvironment (TME), frailty, and ICI response, and irAEs in older patients. This commentary explores the interrelationship between immunosenescence and immunotherapy in older and frail patients with cancer undergoing ICI therapy. Understanding the impact of immunosenescence on treatment response and irAEs, and identifying reliable biomarkers, is crucial for future research in geriatric oncology, as this will possibly facilitate patient stratification and personalized treatment approaches, ultimately improving patient outcomes while minimizing irAE-related risks.

Over the past 50 years, the world has experienced a progressive demographic shift resulting in a higher proportion of older adults in the general population. Aging itself is a complex biological phenomenon, characterized in part by changes in the immune system, known as "immunosenescence", that make older adults more susceptible to infections, cardiovascular and autoimmune diseases, and cancer. Several strategies have been proposed to reverse immunosenescence. These include the use of hormones, cytokines, and thymic factors. Biomodulina T (BT) is a polypeptide fraction derived from bovine thymus. Intervention with BT expands naïve CD4+ T cells while decreasing the frequency of CD4+ and CD8+ T cells expressing PD1 in older adults and patients diagnosed with advanced lung cancer. This brief review aims to present the most recent evidence on the effect of BT on the immune system in older adults and patients diagnosed with advanced lung cancer.

Western and third world countries alike are experiencing population ageing with people living longer. The World Health Organization website states that ‘between 2015 and 2050, the proportion of the world's population over 60 years will nearly double from 12% to 22% reaching 2.1 billion’, and that ‘the number of persons aged 80 years or older is expected to triple between 2020 and 2050 to reach 426 million’. However, the elderly (i.e., those aged over 65 years) are 11 times more likely to develop cancer than younger people; this is illustrated by GLOBOCAN 2020 data showing that greater than 50% of people who had cancer were 65 or older in 2018. This age-related cancer emergence may in part be due to increasing dysregulation of the immune system or “immunosenescence”. Macrophages are pivotal immune cells in maintaining homeostasis and in regulating inflammatory responses during immunological insults, such as cancer, where they can perform anti-tumourigenic functions. Yet, tumour-associated macrophages are well known for their ability to promote tumour growth, with numbers often correlating to cancer progression and poorer outcomes. Macrophages contribute to this by secreting growth and angiogenic factors, and they closely interact with endothelial cells and cancer cells to help shape the tumour microenvironment. During ageing, macrophage response to environmental stimuli becomes dysregulated including impaired anti-tumour functions. Furthermore, increased number of macrophages and precursor cells are observed in lymphoid organs that can supply to tumours with ageing. Such age-related changes, including those to endothelial cells, may promote cancer development and lead to poorer cancer outcomes in elderly people. In this review, we discuss recent findings concerning how macrophages are modulated during healthy ageing and in cancer, with a focus on macrophage and endothelial cell interactions.