Age-related immunological alterations influence resistance to anti-PD1-based therapies in elderly NSCLC patients

Background:Over the past decade, the number of elderly cancer patients has risen, including those with NSCLC, most of whom are older than 60 years old. NSCLC patients undergo anti-PD1-based therapy either alone or in combination with chemotherapy. However, older patients exhibit several baseline changes in their immune systems due to aging that may affect how immunotherapy exerts its effects. Aim:This study aims to evaluate the immune systems of younger(<65 years;young-pts) and older(>65 years;old-pts) NSCLC patients before immunotherapy to determine whether immune aging is associated with the resistance to anti-PD1-based treatments. Methods:Seventy-eight NSCLC patients were enrolled and divided into two age groups:young-pts and old-pts. The patient's immune profile was assessed at baseline by evaluating blood circulating immune cell subsets and soluble immune mediators using cytofluorimetry and Luminex assay. Immune populations and soluble factors were correlated with treatment response and survival outcomes. A cohort of 27 healthy donors (HDs) served as a control. Results:The findings showed that the old-pts group had lower levels of CD3+ and CD4+ T cells and higher levels of CD8+ and Ki67+ T cells than healthy donors (HDs). Survival analysis of NSCLC patients revealed no differences between older and younger patients in the overall population and responders (R). However, among non-responders (NR), older patients had significantly worse survival than younger ones. In fact, older NR patients showed lower levels of central memory T cells and IFN release, along with higher levels of Ki67+ T cells and PMN-(Lox1+)-MDSCs. Meanwhile, R and NR within the age groups differed in CD137+ T cells and PMN(Lox1+)-MDSCs, indicating higher immunosuppression in NR patients, which shifted the immune balance toward suppression, resulting in shorter survival. Conclusions:All the data indicate an immune balance shifted towards immunosuppression and decreased immune surveillance, hallmarks of aging that contribute to therapeuticresistance and decreased survival in the elderly population.