Reinvigorating exhausted CD8⁺ cytotoxic T lymphocytes in the tumor microenvironment and current strategies in cancer immunotherapy

Abstract

Immunotherapy has revolutionized the treatment of cancer in recent years and achieved overall success and long‐term clinical benefit in patients with a wide variety of cancer types. However, there is still a large proportion of patients exhibiting limited or no responses to immunotherapeutic strategy, some of which were even observed with hyperprogressive disease. One major obstacle restricting the efficacy is that tumor‐reactive CD8+ T cells, which are central for tumor control, undergo exhaustion, and lose their ability to eliminate cancer cells after infiltrating into the strongly immunosuppressive tumor microenvironment. Thus, as a potential therapeutic rationale in the development of cancer immunotherapy, targeting or reinvigorating exhausted CD8+ T cells has been attracting much interest. Hitherto, both intrinsic and extrinsic mechanisms that govern CD8+ T‐cell exhaustion have been explored. Specifically, the transcriptional and epigenetic landscapes have been depicted utilizing single‐cell RNA sequencing or mass cytometry (CyTOF). In addition, cellular metabolism dictating the tumor‐infiltrating CD8+ T‐cell fate is currently under investigation. A series of clinical trials are being carried out to further establish the current strategies targeting CD8+ T‐cell exhaustion. Taken together, despite the proven benefit of immunotherapy in cancer patients, additional efforts are still needed to fully circumvent limitations of exhausted T cells in the treatment. In this review, we will focus on the current cellular and molecular understanding of metabolic changes, epigenetic remodeling, and transcriptional regulation in CD8+ T‐cell exhaustion and describe hypothetical treatment approaches based on immunotherapy aiming at reinvigorating exhausted CD8+ T cells.

Identification of tumor microenvironment‑associated immunological genes as potent prognostic markers in the cancer genome analysis project HOPE

“…In the present study, the impressive findings were that memory T cell markers (central ~ effector memory), such as PD-1, CD27 and ICOS, were selected as prognostic factors. In addition to effector-activated CTLs and NK cells, memory marker + T cells should be considered crucial factors because i) PD-1 + T cells can achieve a good balance between good and poor responses by immune checkpoint blockade ( 27 ), and ii) effector memory T cells that proliferate by the stimulation of antigen-presenting cells, can be differentiated into activated effector CTLs ( 34 ). Another important observation was that T cell exhaustion marker genes such as HAVCR22 (TIM3) and TIGIT were included as prognostic markers.…”

“…With advances in genome analysis technologies such as NGSand single-cell RNA sequencing, probable immunological factors belonging to the TME and associated with prognosis have been more intensively, specifically and accurately investigated (24)(25)(26). Beyond the already-known TME factors that might be responsible for the efficacy of cancer immunotherapy, such as positive PD-L1 expression, a high mutational burden and an advanced TIL status, more specific and dynamic biomarkers associated with the immune response have been reported (27)(28)(29). Recently, Kumagai et al demonstrated using cytometry by time of flight (CyTOF) analysis based on single-cell RNA-seq that a balance between Figure 2.…”

“…Ethical approval for the HOPE study was obtained from the Institutional Review Board of Shizuoka Cancer Center (authorization no. [25][26][27][28][29][30][31][32][33]. In total, 1,763 patients with tumors were enrolled until March 2016 and the survival time was observed up to July 2019.…”

Normalization in tumor ecosystem: Opportunities and challenges

“…CD8 + T cells or so‐called CTLs are the most powerful effector cells that provide a backbone of successful immunotherapy (Raskov et al, 2021). The activity of CTLs can be enhanced to establish long‐lasting anticancer responses (Hossain et al, 2021). Macrophages constitute a large population of cells within tumors and their presence is associated generally with a weak prognosis.…”

The immune system also gets tired: Overcoming T-cell exhaustion to potentiate anti-cancer immune responses

“…However, after prolonged antigen exposure, activated T-cells become hyporesponsive and with limited proliferative potential. Hence, T-cell exhaustion may protect tissues from potentially harmful effects of effector CD8 + T-cells 18 .…”