RESUMO
The etiology and effect of age-related immune dysfunction in cancer is not completely understood. Here we show that limited priming of CD8+ T cells in the aged tumor microenvironment (TME) outweighs cell-intrinsic defects in limiting tumor control. Increased tumor growth in aging is associated with reduced CD8+ T cell infiltration and function. Transfer of T cells from young mice does not restore tumor control in aged mice owing to rapid induction of T cell dysfunction. Cell-extrinsic signals in the aged TME drive a tumor-infiltrating age-associated dysfunctional (TTAD) cell state that is functionally, transcriptionally and epigenetically distinct from canonical T cell exhaustion. Altered natural killer cell-dendritic cell-CD8+ T cell cross-talk in aged tumors impairs T cell priming by conventional type 1 dendritic cells and promotes TTAD cell formation. Aged mice are thereby unable to benefit from therapeutic tumor vaccination. Critically, myeloid-targeted therapy to reinvigorate conventional type 1 dendritic cells can improve tumor control and restore CD8+ T cell immunity in aging.
Assuntos
Envelhecimento , Linfócitos T CD8-Positivos , Células Dendríticas , Microambiente Tumoral , Animais , Microambiente Tumoral/imunologia , Linfócitos T CD8-Positivos/imunologia , Camundongos , Células Dendríticas/imunologia , Envelhecimento/imunologia , Camundongos Endogâmicos C57BL , Células Matadoras Naturais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Humanos , Neoplasias/imunologia , Linhagem Celular Tumoral , Feminino , Ativação Linfocitária/imunologiaRESUMO
Aging is one of the biggest risk factors for cancer development. Over 85% of all cancers occur in individuals aged over 55 years, often accompanied by age-associated immune defects. Previous studies on the tumor microenvironment (TME) during aging have identified several factors, such as the roles of fibroblasts, immunosuppression, and metastasis. However, the aging-associated defects in anti-tumor immunity, particularly regarding T cells, remain underexplored. Recent findings by Zhivaki and colleagues suggest that age-related immune defects affecting anti-tumor responses involve reduced levels of CD8+ T cells and compromised dendritic cell (DC) functions such as antigen presentation and migration. Their study demonstrates that a hyperactive DC vaccine can restore DC functions in older mice. Furthermore, these hyperactive DCs, characterized by increased IL-1ß production and better migratory capability to the lymph node, promote the development of cytolytic CD4+ T cells exhibiting Th1-like phenotypes. This research reveals mechanisms underlying the response to hyperactive DC vaccines in older mice and highlights the critical role of cytolytic CD4+ T cells as substitutes for CD8+ T cells in driving anti-tumor immunity and achieving long-term tumor control in older mice.