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 (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.

Deciphering the transcriptomic landscape of tumor-infiltrating CD8 lymphocytes in B16 melanoma tumors with single-cell RNA-Seq

“…Of note, Itgb7 was co-expressed in EM-like cells with the integrin subunit α4 (Itga4) but not with Itgae (CD103), with which ITGB7 dimerizes in tissue-resident T cells. 68 Instead, the α4β7 integrin has been previously shown to mediate lymphocyte migration to gut-associated lymphoid tissue and might have a different function in the context of tumors. 69 Multiple studies have established that PD-1 blockade increases T cell infiltrations in tumors leading to improved anti-tumor control.…”

Deciphering the transcriptomic landscape of tumor-infiltrating CD8 lymphocytes in B16 melanoma tumors with single-cell RNA-Seq

“…At the protein level however, ITGB7 was expressed only by a subset of EM-like cells (Figure 2 C). Of note, Itgb7 was co-expressed in EM-like cells with the integrin subunit a4 (Itga4) but not with Itgae (CD103), with which ITGB7 dimerizes in tissue-resident T cells (Corgnac et al, 2018). Instead, the a4b7 integrin has been previously shown to mediate lymphocyte migration to gut-associated lymphoid tissue and might have a different function in the context of tumors (Denucci, Mitchell and Shimizu, 2009).…”

Chimeric antigen receptor T cell persistence and memory cell formation

“…64 PD-1-mediated expansion of T cells appear to act on CXCR5 + /TIM3 À T cells, as well as tissue and tumorresident memory T cells. 36,66 However, it does not appear to reverse exhaustion in majority of T cells. 15,67 It was recently demonstrated that a proportion of supposedly "exhausted" tumor-infiltrating T cells that express TCF1 (see below) preferentially respond to anti-PD1 treatment and could transform into self-renewing memory cells.…”

“…Tissue resident memory T cells (T RM ) resemble T EM in that they home to nonlymphoid tissue, but T RM express CD103 and CD69, do not recirculate, and are self‐renewing in situ . The degree of infiltration of solid tumors by T RM may be a useful indicator of anti‐cancer responses, including the success of immune checkpoint inhibition . T RM appear to possess direct cytotoxicity, which is dependent on CD103 interactions .…”