Human T lymphocytes at tumor sites

Abstract

CD4⁺ and CD8⁺ T lymphocytes mediate most of the adaptive immune response against tumors. Naïve T lymphocytes specific for tumor antigens are primed in lymph nodes by dendritic cells. Upon activation, antigen-specific T cells proliferate and differentiate into effector cells that migrate out of peripheral blood into tumor sites in an attempt to eliminate cancer cells. After accomplishing their function, most effector T cells die in the tissue, while a small fraction of antigen-specific T cells persist as long-lived memory cells, circulating between peripheral blood and lymphoid tissues, to generate enhanced immune responses when re-encountering the same antigen. A subset of memory T cells, called resident memory T (T_RM) cells, stably resides in non-lymphoid peripheral tissues and may provide rapid immunity independently of T cells recruited from blood. Being adapted to the tissue microenvironment, T_RM cells are potentially endowed with the best features to protect against the reemergence of cancer cells. However, when tumors give clinical manifestation, it means that tumor cells have evaded immune surveillance, including that of T_RM cells. Here, we review the current knowledge as to how T_RM cells are generated during an immune response and then maintained in non-lymphoid tissues. We then focus on what is known about the role of CD4⁺ and CD8⁺ T_RM cells in antitumor immunity and their possible contribution to the efficacy of immunotherapy. Finally, we highlight some open questions in the field and discuss how new technologies may help in addressing them.

Keywords: Cancer immunology; Immunotherapy; Memory T cell differentiation; T cell homing; Tissue-resident T cells; Trm cells.

Fig. 1

T cell trafficking in lymphoid and non-lymphoid tissues. T cells enter non-lymphoid tissues exclusively through arterial blood and exit either with lymph to reach lymph nodes via the afferent lymphatic vessels, or with venous blood. T cells can enter lymph nodes also directly from the arterial circulation through the high endothelial venules (HEV) and return to the blood circulation through the efferent lymphatic vessels and the lymph ducts

Fig. 2

T cell activation and migration to non-lymphoid tissues. (a) Antigens are presented to naïve T cells either by migratory DCs, which collect antigens in the peripheral tissues, mature, and migrate into the lymph nodes, or by lymph node-resident DCs that take up antigens transported in solution with the lymph. (b) Activated T cells exit from lymph nodes reaching first venous and then arterial blood and home into inflamed tissue chasing a gradient of inflammatory chemokines thanks to the expression of the corresponding chemokine receptors. Once in the proximity of the inflamed tissue, T cells adhere to the vascular endothelium first through weak interactions with endothelial selectins, such as E- and P-selectin, and then arresting their rolling by binding with integrins to endothelial adhesion molecules. Stable adhesion is followed by extravasation guided by the chemokine gradient and the upregulation of CD69 expression. (c) Upon activation naïve T cells start to proliferate and differentiate into effector cells, which migrate to peripheral tissues where they perform their effector function. Once the antigen has been eliminated, the large majority of effector cells die by apoptosis, while a small fraction of antigen-specific T cells persists as T_CM, T_EM, or T_RM cells, which are characterized by a tropism toward different anatomic sites, to provide systemic and local long-term protection

Fig. 3

T_RM cell differentiation. Naïve T cells can be reversibly preconditioned in homeostasis and imprinted during activation by migratory DCs to become T_RM cells through TGF-β signaling. Migratory DCs can also instruct T cells to home into the same non-lymphoid tissue they came from. For instance, intestinal and cutaneous migrating DCs, by metabolizing respectively vitamin A and vitamin D, induce the expression of chemokine receptors guiding activated T cell homing into the gut and the skin. Recently activated effector T cells reach the inflamed non-lymphoid tissues through arterial circulation and extravasate also thanks to the competition between CD69 and S1PR1. Here, a subset of effector T_RM precursor cells upregulates the expression of tissue-retention molecules (e.g., CD103, CD49a, and CXCR6) in response to TGF-β and IL-12, differentiating into long-lived T_RM cells. Re-encountering the cognate antigen presented by professional and non-professional antigen-presenting cells may enhance the establishment of T_RM cells

Fig. 4

Generation of tumor-specific effector and memory T cells. Tumor antigens released by cancer cells are collected by dendritic cells and presented to naïve T cells in lymph nodes. Differentiated tumor-specific effector T cells migrate to the tumor site where they perform their effector function. Effector CD8⁺ and CD4⁺ T cells exert their anti-tumor activity by directly killing tumor cells and providing help to other immune cells, while T_REG and T_R1 cells suppress the immune response. Immune-mediated cancer cell death can induce the release of more tumor antigens and sustain anti-tumor immunity

Fig. 5

Tumor and immune system co-evolution. Tumor-specific T_RM cells can be generated following the effector response against the first immunogenic cancer cells. During the equilibrium phase of tumor development, T_RM cells can kill cancer cells and contribute to the control of tumor growth. However, the tumor can escape immune surveillance, including that from T_RM cells, and generate an immunosuppressive microenvironment. Chemotherapy and immunotherapy can reactivate the anti-tumor immune response: chemotherapy by inducing the release of tumor neoantigens, which can trigger the generation of new tumor-specific effector T cells; immunotherapy by reactivating the effector function of dysfunctional memory T cells