Abstract
The impact of age on the clinical benefit of anti-PD1 immunotherapy in advanced melanoma patients has been evolving recently. Due to a reduced immune function in elderly patients, young patients with a robust immune system are theoretically expected to benefit more from the treatment approach. However, in contrast to this hypothesis, recent studies in patients with metastatic melanoma have demonstrated that immunotherapy, especially with anti-PD1 treatment, is less effective in patients below 65 years, on average, with significantly lower responses and reduced overall survival compared to patients above 65 years of age. Besides, data on young patients are even more sparse. Hence, in this review, we will focus on age-dependent differences in the previously described resistance mechanisms to the treatment and discuss the development of potential combination treatment strategies for enhancing the anti-tumor efficacy of anti-PD1 or PDL1 treatment in young melanoma patients.
Highlights
Compared to other cancers, the average age at diagnosis of melanoma among women is comparatively low at 60 years
The percentage of CD8+ T cells in melanoma tumor microenvironment (TME) was significantly lower in younger patients under the age of 66 years, which correlated with increased numbers in tumor-infiltrating FOXP3 regulatory T cells, indicating that tumors in young patients are accommodated with a more vital immunosuppressive environment with higher frequencies of potent Tregs
The molecular mechanisms underlying sex-based differences in non-responsiveness to immune checkpoint inhibitors (ICIs) have been recently characterized in mouse models, such as estrogen-mediated recruitment of myeloid-derived suppressive cells (MDSCs) and Tregs to the TME, that are known to be involved in resistance to ICIs [69]
Summary
The average age at diagnosis of melanoma among women is comparatively low at 60 years. Among the available systemic anti-cancer treatments for melanoma, immunotherapy with immune checkpoint inhibitors, such as anti-programmed cell death protein-1 (anti-PD1) or programmed cell death protein ligand-1 (PDL1), has demonstrated remarkable clinical benefits, increasing life expectancy in advanced disease patients [5,6,7,8]. A report using the National cancer database of around twelve thousand advanced melanoma patients receiving immunotherapy with anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA4) and/or anti-PD1 treatment showed an apparent decrease in OS of younger patients under the age of 60 compared to elderly patients of above 60 years. In this review, we will focus on age-dependent differences in the previously described mechanisms of resistance to PD1/PDL1 inhibitors (Figure 1) and discuss the development of potential combination treatment strategies for enhancing the anti-tumor efficacy of anti-PD1/PDL1 treatment in younger melanoma patients. Figure 1F.igAugree-re1l.atAedged-irffeelraetnecdesdiinffcelirneincacleasnidnmcloilneiccuallarafnadctomrsoalsescoucliaartedfawctiothrsanatsis-PoDci1atteredatwmietnht oaunttcio-PmDe1intrmeeatta-static melanommaenptaotiuentctso.me in metastatic melanoma patients
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