The function and dysfunction of memory CD8⁺ T cells in tumor immunity

Abstract

The generation and maintenance of CD8 T cell memory is crucial to long-term host survival, yet the basic tenets of CD8 T cell immunity are still being established. Recent work has led to the discovery of tissue-resident memory cells and refined our understanding of the transcriptional and epigenetic basis of CD8 T cell differentiation and dysregulation. In parallel, the unprecedented clinical success of immunotherapy has galvanized an intense, global research effort to decipher and de-repress the anti-tumor response. However, the progress of immunotherapy is at a critical juncture, since the efficacy of immuno-oncology agents remains confined to a fraction of patients and often fails to provide durable benefit. Unlocking the potential of immunotherapy requires the design of strategies that both induce a potent effector response and reliably forge stable, functional memory T cell pools capable of protecting from recurrence or relapse. It is therefore essential that basic and emerging concepts of memory T cell biology are rapidly and faithfully transposed to advance therapeutic development in cancer immunotherapy. This review highlights seminal and recent reports in CD8 T cell memory and tumor immunology, and evaluates recent data from solid cancer specimens in the context of the key paradigms from preclinical models. We elucidate the potential significance of circulating effector cells poised downstream of neoantigen recognition and upstream of T cell dysfunction and propose that cells in this immunological 'sweet spot' may be key anti-tumor effectors.

Single-cell analyses identify tobacco smoke exposure-associated, dysfunctional CD16+ CD8 T cells with high cytolytic potential in peripheral blood

“…Senescence can be induced as the result of telomere shortening or non-telomeric DNA damage (Akbar and Henson, 2011), both of which have been reported to occur in smokers (Song et al, 2010;Valdes et al, 2005). Accelerated immune system aging accompanies T cell senescence and can manifest as impaired immunological memory (Reading et al, 2018), which could contribute to attenuated immune responses in smokers. Of note, GFI1, a transcriptional repressor of IL-7Ra that drives terminal differentiation of CD8 T cells (Ligons et al, 2012), was elevated in CD8T-8 cells.…”

Combining DNA Vaccine and AIM2 in H1 Nanoparticles Exert Anti-Renal Carcinoma Effects via Enhancing Tumor-Specific Multi-functional CD8+ T-cell Responses

“…Most therapies of anti-tumor immune responses are directed toward enhancing the CD8 þ T-cell responses, as CD8 þ T cells are specialized for lytic function (29). To evaluate whether H1-pAIM2/pCAIX vaccine enhanced CAIX-specific CD8 T-cell responses, CD8 T-cell proliferation, CTL activity, and functional CD8 þ T cells were assessed in various immunization groups.…”

Immunotherapy of CT26 murine tumors is characterized by an oligoclonal response against the AH1 tumor rejection antigen

“…In mice, cures of CT26 colorectal cancer has been described in mice receiving immune checkpoint inhibitors (4), antibody-cytokine fusions (5,6) or a combination of these two treatment modalities (7). CD8+ T cells play a crucial role in the tumor rejection process (8,9). Highly-mutated tumors (e.g., melanomas and non-small cell lung cancers) typically respond better to immune checkpoint inhibitors and it is likely that neo-antigens (i.e., mutated peptides presented on HLA class I molecules) contribute to tumor rejection (10,11).…”