Immune senescence in non-small cell lung cancer management: therapeutic relevance, biomarkers, and mitigating approaches

ABSTRACT

Introduction

Lung cancer and mainly non-small cell lung cancer (NSCLC) still remain a prevalent malignancy worldwide despite sustained screening approaches. Furthermore, a significant proportion of the cases are diagnosed at advanced stages when conservative therapy is often unsuccessful. Cell senescence is an endogenous antitumor weapon but when it is upregulated exerts opposite activities favoring tumor metastasizing and poor response to therapy. However, little is known about this dangerous relationship between cell senescence and NSCLC outcome or on potential approaches to mitigate its unfavorable consequences.

Areas covered

We discuss cell senescence focusing on immune senescence, its cell and humoral effectors (namely immune senescence associated secretory phenotype-iSASP), its impact on NSCLC outcome, and its biomarkers. Senotherapeutics as mitigating approaches are also considered based on the availability of experimental data pertinent to NSCLC.

Expert opinion

Characterization of NSCLC subsets in which immune senescence is a risk factor for poor prognosis and poor therapeutic response might be very helpful in supporting the addition of senotherapeutics to conventional cancer therapy. This approach has the potential to improve disease outcome but more studies in this area are necessary.

KEYWORDS:

• Cell senescence
• exhausted T cells
• non-small cell lung cancer
• poor prognosis
• palliative care
• senotherapeutics
• senolytics
• senomorphics
• SASP
• supportive care

Article highlights

• Lung cancer (mainly NSCLC) is still the most prevalent malignancy despite sustained screening programs and consequently the prevalence of advanced stages at first diagnosis is relatively high.

• Senescence in general and immune senescence in particular can be considered up to a point as an endogenous antitumor mechanism having as effectors adaptive and immune cells and their cytokine/chemokine byproducts labelled as senescence associated secretory phenotype (iSASP) .

• However ‘pathologic’ immune senescence can exist in such patients and can be related with increase invasiveness and with poor therapeutic response to onco treatments. This relationship is worth being considered especially in the setting of immune checkpoint inhibitors which are expensive and not widely available.

• Therefore immune senescence is worth being evaluated and mitigated with senotherapeutics.

• Senotherapeutics are broadly classified into senolytics (which are able to induce apoptosis of the senescent cells) and senomorphics (which are able to inhibit SASP) and many of them are currently investigated experimentally in lung cancer.

• Some of the experimental data report on the potential of such therapies to restore response to onco therapies especially in aggressive subtypes of NSCLC and therefore their further evaluation in a clinical setting is supported.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The drafting of this paper was funded with the research grant contract 9990/2022 provided by the University of Medicine and Pharmacy Grigore T Popa Iasi, Romania.