Abstract
Cancer immunotherapy is aimed at stimulating tumor-specific cytotoxic T lymphocytes and their subsequent trafficking so that they may reach, and persist in, the tumor microenvironment, recognizing and eliminating malignant target cells. Thus, characterization of the phenotype and effector functions of CD8+ T lymphocytes infiltrating human solid tumors is essential for better understanding and manipulating the local antitumor immune response, and for defining their contribution to the success of current cancer immunotherapy approaches. Accumulating evidence indicates that a substantial subpopulation of CD3+CD8+ tumor-infiltrating lymphocytes are tissue resident memory T (TRM) cells, and is emerging as an activated tumor-specific T-cell subset. These TRM cells accumulate in various human cancer tissues, including non-small-cell lung carcinoma (NSCLC), ovarian and breast cancers, and are defined by expression of CD103 [αE(CD103)β7] and/or CD49a [α1(CD49a)β1] integrins, along with C-type lectin CD69, which most likely contribute to their residency characteristic. CD103 binds to the epithelial cell marker E-cadherin, thereby promoting retention of TRM cells in epithelial tumor islets and maturation of cytotoxic immune synapse with specific cancer cells, resulting in T-cell receptor (TCR)-dependent target cell killing. Moreover, CD103 integrin triggers bidirectional signaling events that cooperate with TCR signals to enable T-cell migration and optimal cytokine production. Remarkably, TRM cells infiltrating human NSCLC tumors also express inhibitory receptors such as programmed cell death-1, the neutralization of which, with blocking antibodies, enhances CD103-dependent TCR-mediated cytotoxicity toward autologous cancer cells. Thus, accumulation of TRM cells at the tumor site explains the more favorable clinical outcome, and might be associated with the success of immune checkpoint blockade in a fraction of cancer patients.
Highlights
CD8+ T lymphocytes play an essential role in defense against cancers through recognition by T-cell receptors (TCR) of specific antigenic peptides presented on the surface of malignant cells by major histocompatibility complex class I (MHC-I) molecules, and elimination of the tumor target, mainly by releasing the content of cytolytic granules containing perforin and granzymes
We focus on CD8+ TRM cells accumulating in human solid tumors, mainly non-smallcell lung carcinoma (NSCLC), and current insight implicating CD103 integrin in regulating TRM functions and cytotoxic T lymphocytes (CTL)-mediated antitumor immune responses, with potential prognosis and immunotherapeutic applications
We further showed that phosphorylated-integrin-linked kinase (ILK) interacted with the CD103 subunit intracellular domain, resulting in phosphorylation of protein kinase B (PKB)/AKT, thereby initiating integrin inside-out signaling leading to activation of CD103 and strengthening of CD103-E-cadherin adhesion
Summary
Accumulating evidence indicates that a substantial subpopulation of CD3+CD8+ tumor-infiltrating lymphocytes are tissue resident memory T (TRM) cells, and is emerging as an activated tumor-specific T-cell subset. These TRM cells accumulate in various human cancer tissues, including non-small-cell lung carcinoma (NSCLC), ovarian and breast cancers, and are defined by expression of CD103 [αE(CD103)β7] and/or CD49a [α1(CD49a)β1] integrins, along with C-type lectin CD69, which most likely contribute to their residency characteristic. TRM cells infiltrating human NSCLC tumors express inhibitory receptors such as programmed cell death-1, the neutralization of which, with blocking antibodies, enhances CD103-dependent TCR-mediated cytotoxicity toward autologous cancer cells.
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