The Potential of Tissue-Resident Memory T Cells for Adoptive Immunotherapy against Cancer

Abstract

Tissue-resident memory T cells (T_RM) comprise an important memory T cell subset that mediates local protection upon pathogen re-encounter. T_RM populations preferentially localize at entry sites of pathogens, including epithelia of the skin, lungs and intestine, but have also been observed in secondary lymphoid tissue, brain, liver and kidney. More recently, memory T cells characterized as T_RM have also been identified in tumors, including but not limited to melanoma, lung carcinoma, cervical carcinoma, gastric carcinoma and ovarian carcinoma. The presence of these memory T cells has been strongly associated with favorable clinical outcomes, which has generated an interest in targeting T_RM cells to improve immunotherapy of cancer patients. Nevertheless, intratumoral T_RM have also been found to express checkpoint inhibitory receptors, such as PD-1 and LAG-3. Triggering of such inhibitory receptors could induce dysfunction, often referred to as exhaustion, which may limit the effectiveness of T_RM in countering tumor growth. A better understanding of the differentiation and function of T_RM in tumor settings is crucial to deploy these memory T cells in future treatment options of cancer patients. The purpose of this review is to provide the current status of an important cancer immunotherapy known as TIL therapy, insight into the role of T_RM in the context of antitumor immunity, and the challenges and opportunities to exploit these cells for TIL therapy to ultimately improve cancer treatment.

Keywords: CD8+ memory T cells; Cytotoxic T cells; T cell exhaustion; adoptive cell therapy; immunotherapy; tissue-resident memory T cells.

Figure 1

The differentiation pathway of exhausted T cells and tissue-resident memory T cells in the tumor microenvironment. (A) Upon activation, precursor exhausted T (T_EX) cells expressing the surface molecules SLAMF6, CXCR5 and CD69 and the transcription factors TCF-1 and T-BET migrate from the T cell zones of the secondary lymphoid organs (SLO) towards the tumor microenvironment (TME). (B) In the TME, precursor T_EX differentiate into terminal T_EX, which express the transcription factors TOX, BLIMP-1, Eomes and NR4A, and have an impaired ability to produce cytokines (e.g., IFN-γ, TNF-α and IL-2), but an increased production of cytotoxic molecules (e.g., granzyme B). Terminal T_EX also upregulate the expression of inhibitory receptors, such as PD-1, CTLA-4, LAG-3 and TIM-3. Precursor T_EX may also give rise to intratumoral tissue-resident memory T (T_RM) cells expressing the transcription factors BLIMP-1, HOBIT and RUNX3 and the extracellular molecules CD69, CD103 and CD49a. Similar to terminal T_EX, T_RM upregulate inhibitory receptors and downregulate cytokine responses. In contrast, T_RM appear to maintain expression of cytotoxic molecules. Abbreviations: BLIMP-1, B lymphocyte-induced maturation protein 1; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; CX3CR1, CX3C chemokine receptor 1; CXCR5, C-X-C chemokine receptor type 5; GZMB, granzyme B; HOBIT, homolog of Blimp-1 in T cells; IFN-γ, interferon gamma; IL-2, interleukin 2; LAG-3, lymphocyte-activation gene 3; NR4A, nuclear hormone receptor 4A; PD-1, programmed cell death protein 1; PRF1, perforin 1; RUNX3, runt-related transcription factor 3; SLAMF6, SLAM family member 6; T-BET, T-box transcription factor 21; TCF-1, T-cell factor 1; TIM-3, T-cell immunoglobulin and mucin domain 3; TNF-α, tumor necrosis factor alpha; TOX, thymocyte selection-associated high-mobility group box protein.

Figure 2

Strategies of conventional and candidate adoptive T cell therapy. (A) TIL therapy involves the isolation and expansion of tumor-infiltrating lymphocytes (TILs) from tumor tissue for reinfusion into the cancer patient. The current strategy employs unfractionated TILs that may include central memory T (T_CM) cells, effector memory T (T_EM) cells, tissue-resident memory T (T_RM) cells and precursor and terminal exhausted T (T_EX) cells (panel 1). (B) A potential novel strategy of TIL therapy is to select T_CM or precursor T_EX, which have high potential to form the complete spectrum of T cell subsets. However, these precursor cells may have limited potential to form T_RM (panel 2). Therefore, another approach to establish improved TIL therapy may be to select T_RM cells from tumor tissue, which have intrinsic capacity to reform T_RM (panel 3). Both strategies may have the potential to improve the efficacy of TIL therapy to counter tumor growth.