The Emerging Role of CD8+ Tissue Resident Memory T (TRM) Cells in Antitumor Immunity: A Unique Functional Contribution of the CD103 Integrin

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 (T_RM) cells, and is emerging as an activated tumor-specific T-cell subset. These T_RM 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 [α_E(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 T_RM 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, T_RM 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 T_RM 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.

Keywords: CD103 integrin; CD8 tissue resident memory T (TRM) cells; cancer immunotherapy; cytotoxic T lymphocytes; onco-immunology.

Figure 1

TGF-β induces CD103 expression in tumor-specific T cells and participates in integrin bidirectional signaling. Left: TGF-β controls CD103 expression in tumor antigen (Ag)-specific T cells upon interaction of T-cell receptor (TCR) with specific tumor peptide–major histocompatibility complex class I complexes, via a Smad-dependent pathway. TGF-β binds to TGFBR at the surface of CD8⁺ T lymphocytes and leads to recruitment and phosphorylation of Smad2 and Smad3 and their subsequent nuclear translocation. Transcription factors NFAT-1, translocated into the nucleus upon TCR engagement, and Smad2/3 bind to promoter and enhancer elements of the ITGAE gene, which encodes the CD103 (α_E) subunit, and activates CD103 expression (29). Right: TGF-β participates in CD103 intracellular signaling via a non-Smad-dependent pathway. Interaction of TGF-β with TGFBR on CD8⁺CD103⁺ T_RM cells induces recruitment and phosphorylation of integrin-linked kinase (ILK). Phosphorylated (P)-ILK interacts with the CD103 subunit intracellular domain, resulting in phosphorylation of protein kinase B/AKT and initiating integrin inside-out signaling leading to activation of CD103 (30). CD103-E-cadherin tight adhesion initiates an outside-in signal by promoting phosphorylation of paxillin (Pax) and Pyk2, and subsequent binding of phosphorylated-paxillin to the α_E subunit tail where a phosphorylatable Ser (S) in the ES¹¹⁶³IRKAQL motif plays an important role (80). Adhesive interaction of E-cadherin with CD103 also triggers activation of PI3K/extracellular signal-regulated kinase (ERK) and phospholipase C/PKC pathways (60), providing intracellular signals that promote CD8⁺ T_RM effector functions, including actin cytoskeleton reorganization, T-cell spreading and migration, cytokine release and polarized exocytosis of cytotoxic granules leading to target cell destruction.

Figure 2

Adoptive transfer of CD8⁺CD103⁺ T_RM cells for cancer immunotherapy. CD8⁺CD103⁺ T_RM cells, suspected to express tumor-reactive T-cell receptors, are isolated from tumor-infiltrating lymphocytes (TIL), amplified ex vivo in the presence of T-cell growth factors, including IL-2, and then reinjected into cancer patients, in combination or not with immune checkpoint inhibitors, such as anti-programmed cell death-1, to reverse T-cell exhaustion and optimize the antitumor cytotoxic T lymphocyte response.