Effects of extracellular pH and hypoxia on the function and development of antigen-specific cytotoxic T lymphocytes

Abstract

The major effector cells for cellular adaptive immunity are CD8(+) cytotoxic T lymphocytes (CTLs), which can recognize and kill virus-infected cells and tumor cells. Although CTLs exhibit strong cytolytic activity against target cells in vitro, a number of studies have demonstrated that their function is often impaired within tumors. Nevertheless, CTLs can regain their cytotoxic ability after escaping from the tumor environment, suggesting that the milieu created by tumors may affect the function of CTLs. As for the tumor environment, the patho-physiological situation present in vivo has been shown to differ from in vitro experimental conditions. In particular, low pH and hypoxia are the most important microenvironmental factors within growing tumors. In the present study, to determine the effect of these factors on CTL function in vivo, we examined the cytolytic activity of CTLs against their targets using murine CTL lines and the induction of these cells from memory cells under low pH or hypoxic conditions using antigen-primed spleen cells. The results indicated that both cytotoxic activity and the induction of functional CTLs were markedly inhibited under low pH. In contrast, in hypoxic conditions, although cytotoxic activity was almost unchanged, the induction of CTLs in vitro showed a slight enhancement, which was completely abrogated in low pH conditions. Therefore, antigen-specific CTL functions may be more vulnerable to low pH than to the oxygen concentration in vivo. The findings shown here provide new therapeutic approaches for controlling tumor growth by retaining CTL cytotoxicity through the maintenance of higher pH conditions.

Metabolism and Gut Microbiota in Cancer Immunoediting, CD8/Treg Ratios, Immune Cell Homeostasis, and Cancer (Immuno)Therapy: Concise Review

“…Furthermore, as tumors outgrow their blood supply and form hypoxic regions, reliance on glycolysis as a primary mode of glucose metabolism leads to microenvironment acidification through accumulation of lactic acid. Acidic TME affects immune cell polarization, decreasing antitumor immunity, disrupting T‐cell motility, and causing loss of cytotoxic function in CD8+T cells . Furthermore, lactate metabolism in oxygenated cancer cells has been shown to increase glutaminolysis , further promoting competition for resources between cancer and immune cells, the outcome of which can determine not only the function but also composition of immune cells in the TME.…”

Intratumoral Hypoxia Reduces IFN-γ–Mediated Immunity and MHC Class I Induction in a Preclinical Tumor Model

“…Similarly, other in vivo studies demonstrate preferential localization of T cells away from hypoxic tumor zones, suggesting a possible immune escape mechanism used by tumor cells (20)(21)(22). However, some studies have demonstrated that T cells are better killers when activated at lower than normal oxygen conditions (23) and that such cells can enhance tumor rejection (24)(25)(26)(27). Additionally, another study demonstrated increased production of the lytic molecules perforin and granzyme upon constitutive activation of hypoxia inducible factor-1 (HIF-1), the predominate transcription factor for hypoxia signaling, indicating that hypoxic T cells are better killers (28,29).…”

Healing Processes in Cancellous Bone

“…6,9,[57][58][59] Inflammatory cells however are more resilient to such conditions and can infiltrate the hematoma. [60][61][62] Once inside the hematoma, inflammatory cells send signals to attract other cell types (e.g. mesenchymal cells) to migrate to the zone of injury.…”