Egress of resident memory T cells from tissue with neoadjuvant immunotherapy: Implications for systemic anti-tumor immunity

Abstract

Introduction: Resident memory T (T_RM) cells are embedded in peripheral tissue and capable of acting as sentinels that can respond quickly to repeat pathogen exposure as part of an endogenous anti-microbial immune response. Recent evidence suggests that chronic antigen exposure and other microenvironment cues may promote the development of T_RM cells within solid tumors as well, and that this T_RM phenotype can sequester tumor-specific T cells into tumors and out of circulation resulting in limited systemic antitumor immunity. Here, we perform a review of the published English literature and describe tissue-specific mediators of T_RM cell differentiation in states of infection and malignancy with special focus on the role of TGF-β and how targeting TGF-β signaling could be used as a therapeutical approach to promote tumor systemic immunity.

Discussion: The presence of T_RM cells with antigen specificity to neoepitopes in tumors associates with positive clinical prognosis and greater responsiveness to immunotherapy. Recent evidence indicates that solid tumors may act as reservoirs for tumor specific T_RM cells and limit their circulation - possibly resulting in impaired systemic antitumor immunity. T_RM cells utilize specific mechanisms to egress from peripheral tissues into circulation and other peripheral sites, and emerging evidence indicates that immunotherapeutic approaches may initiate these processes and increase systemic antitumor immunity.

Conclusions: Reversing tumor sequestration of tumor-specific T cells prior to surgical removal or radiation of tumor may increase systemic antitumor immunity. This finding may underlie the improved recurrence free survival observed with neoadjuvant immunotherapy in clinical trials.

Figure 1:. Mechanisms of development and maintenance of T_RM cells.

Tissue-specific dendritic cells (DCs) migrate to the draining lymph nodes (dLN) where they present antigens to naïve T cells. Once primed, these T cells have the capacity to become CD8⁺ T_RM precursors and migrate to the injured tissue, following a chemotactic gradient. In the tissue, exposure to transforming growth factor beta (TGF-β) initiates the resident memory program, namely by driving the expression of the integrin alpha E (ITGAE/CD103) that binds to E-cadherin expressed by the tissue, enforcing retention. TGF-β is also important in driving the general transcriptional profile of T_RM cells, which requires the expression of Hobit, Blimp-1, Runx3 and Notch and downregulation of Tcf-1, Eomes, T-bet and Klf2. T_RM cells are often characterized by the expression of immune checkpoint receptors associated with T cell exhaustion such as Lag-3, TIM-3, CTLA-4, and PD-1.

Figure 2:. Neoadjuvant therapy as a strategy to induce recirculation of T_RM-like cells and systemic immunity against cancer.

Through expression of tissue resident markers such as CD103, exhausted, dysfunctional CD8⁺ T cells reside in tumor tissue. PD-1 targeting immune checkpoint blockade with or without TGF- β blockade enhance egress of CD8⁺ T cells out of the tumor and into circulation prior to surgical removal of the tumor. This treatment result may increase the systemic anti-tumor immunity of the patient and improve recurrence free survival.