The role of aging and metabolism in the regulation of T cell immunity

Abstract

Functional deterioration of the adaptive immune system is a cardinal feature of the natural aging process and coincides with a sharp increase in the incidence of cancer. Although immune checkpoint blockade (ICB) has revolutionized the landscape of cancer therapy by providing durable tumor regression and overall survival, how aging impacts anti-tumor immunity and the activity of ICB is poorly understood. In addition to age-associated T cell dysfunction, metabolic barriers play a prominent role in the subversion of anti-tumor immune responses. However, the metabolic pathways required for effective anti-tumor immunity and successful re-invigoration of T cell function following ICB therapy are largely unknown.

By systemically dissecting the consequences of aging on anti-tumor immunity, we identified the loss of tumor antigen-specific CD8+ T cells as a primary feature driving tumor progression and resistance to immunotherapy in aged mice. Provision of tumor-matching clones elicits anti-tumor activity and sensitizes aged mice to ICB with anti-PD-1 therapy. Our results resolve a long standing mystery as to why mice beyond a certain age are recalcitrant to ICB therapy and highlight the importance of considering antigen specificity in studies of anti-tumor T cell responses in aged animals.

Additionally, we identify and functionally validate asparagine (Asn) metabolism as a novel regulator of the anti-tumor T cell response to PD-1 blockade. Remarkably, therapeutic Asn supplementation provides metabolic support to CD8+ T cells reinvigorated by anti-PD-1, resulting in enhanced tumor eradication and increased survival. We show that extracellular Asn bioavailability also represents a metabolic vulnerability for CD4+ helper T cells. Depletion of extracellular Asn impairs the activation, proliferation and differentiation of CD4+ T cells into helper lineages by restricting protein synthesis and dysregulating mitochondrial fitness. We demonstrate that Asn depletion through asparaginase treatment therapeutically ameliorates autoimmunity driven by pathogenic CD4+ T helper cells. These results identify Asn metabolism a key metabolic node for functional responses of T cells.

Taken together, our studies resolve an important conceptual gap in the aging cancer immunology field by identifying the loss of tumor antigen-specific T cells as a fundamental barrier for eliciting protective anti-tumor immunity in aged mice and reveal a requisite role for Asn metabolism in the propagation of functional T cell responses.