Immunosenescence and cancer immunotherapy.

Abstract

42 Background: Geriatric oncology, important for the ever-increasing numbers of elderly cancer patients, has thus far focused primarily on tolerance to chemotherapy. With the advent of breakthrough immunomodulatory antibody treatments relying on the patient´s own immune system to control the tumor, the issue of immunosenescence becomes extremely important. There is increasingly a valid concern that anti-cancer immunity may be compromised in the elderly due to i) their low amounts of naïve T-cells (leading to holes in the repertoire for neoantigens) and ii) “exhaustion” of potentially tumor-specific memory T-cells. Encouragingly, but only anecdotally, accumulated clinical experience (thus far, limited to melanoma treated with anti-CTLA-4 antibodies) suggests that advanced aged does not result in decreased responses or increased side effects. However, the fraction of patients experiencing clinical benefit was low, and broader and more detailed studies focusing on the age question are required. Methods: In our own work, we have established prognostic phenotypic and functional “immune signatures” using peripheral blood from younger melanoma and breast cancer patients, which comprise phenotypic T-cell and myeloid-derived suppressor cell quantification and measurement of pro- and anti-inflammatory CD4+ and CD8+ T-cell responses to shared tumor antigens such as NY-ESO-1 and Her2 in vitro using intracytoplasmic flow cytometry to detect 6 cytokines simultaneously. Results: We found that these peripheral immune signatures were equally prognostic in older patients ( > 80 years of age). Conclusions: We therefore conclude that immunosenescence should not be a barrier to anti-tumor immunity in elderly people treated with immunomodulatory antibodies, at least for responses targeting shared tumor antigens. It remains to be established whether responses to tumor neoantigens are compromised by immunosenescence. Given the current emphasis on neoantigen responsiveness, this remains a concern.