Immune Aging in Responsiveness to Checkpoint Blockade Immunotherapies

衰老对免疫有深远的影响（免疫老化），有报道说更容易

Aging has a profound influence on immunity (Immune aging), with reports of greater susceptibility to cancers and infections, lower vaccine efficacy, and weakened immunity against persistent infections with advancing age. Nonetheless, surprisingly little is known about how cancer immunity and immunotherapy outcomes are altered with immune aging. The SEER program (Surveillance Epidemiology End Result, https://seer.cancer.gov) estimates approximately 38.4 percent of men and women will be diagnosed with cancer at some point during their lifetime. In the face of these alarming statistics, last decade has heralded remarkable new immune-based therapies with potent clinical efficacy. A frontline FDA-approved therapy - checkpoint blockade immunotherapy (CBI) using antibodies that block a dominant negative regulator of T cell responses, PD-1 or PD-L 1 - has proven to be a real tour de force in treating several refractory solid tumors (such as RCC, NSCLC, MCC and melanoma). However, not all patients respond to PD-1 CBI, the degree of responsiveness is variable, and the biomarkers predictive of therapeutic efficacy remain largely elusive. The goal of this project is to unravel the immunometabolic mechanisms underlying the widely disparate efficacy of PD-1 CBI, with "immune aging". Based on several documented immune defects with age, we predicted that therapeutic efficacy of PD-1 CBI might be compromised with advancing age. Indeed, recent studies from our laboratory and others' demonstrate impaired responsiveness to PD-1 CBI in aged versus young hosts. Mechanistically, tantalizing new data show that CD8 T cells that respond most efficiently to PD-1 CBI are newly (or less) exhausted by virtue of being recently recruited into the immune response. Since na"ive CD8 T cell numbers, repertoire and function decline with age (due to the combined result of developmentally-programmed thymic atrophy and past medical history), we propose that immune aging-related decline in na·ive CD8 T cell quantity and quality leads to a reduction in the pool of less exhausted tumor-reactive CD8 T cells more amenable to functional rescue, thus compromising the efficacy of PD-1 checkpoint blockade therapy. The goal of this proposal is to understand how immune aging related decline in na"ive CD8 T cell repertoire and/or metabolic function impacts the extent of exhaustion and therapeutic efficacy of PD-1 CBI. We further aim to define the metabolic determinants of T cell rejuvenation potential - as regulated by age-related alterations in T cell exhaustion - and evaluate novel strategies to potentially augment the therapeutic efficacy of PD-1 CBI by promoting the development of less exhausted cells that are more responsive to CBI through alterations in na·ive T cell thymic output, activation, expansion or cytotoxic function. By elucidating immune aging-related mechanisms of T cell exhaustion that influence therapy outcomes, these studies will provide insight into the disparity in patient responsiveness, and will offer novel strategies to augment therapeutic efficacy.