Turning cold tumors into hot tumors by improving T-cell infiltration

Abstract

Immunotherapy, represented by immune checkpoint inhibitors (ICIs), has greatly improved the clinical efficacy of malignant tumor therapy. ICI-mediated antitumor responses depend on the infiltration of T cells capable of recognizing and killing tumor cells. ICIs are not effective in "cold tumors", which are characterized by the lack of T-cell infiltration. To realize the full potential of immunotherapy and solve this obstacle, it is essential to understand the drivers of T-cell infiltration into tumors. We present a critical review of our understanding of the mechanisms underlying "cold tumors", including impaired T-cell priming and deficient T-cell homing to tumor beds. "Hot tumors" with significant T-cell infiltration are associated with better ICI efficacy. In this review, we summarize multiple strategies that promote the transformation of "cold tumors" into "hot tumors" and discuss the mechanisms by which these strategies lead to increased T-cell infiltration. Finally, we discuss the application of nanomaterials to tumor immunotherapy and provide an outlook on the future of this emerging field. The combination of nanomedicines and immunotherapy enhances cross-presentation of tumor antigens and promotes T-cell priming and infiltration. A deeper understanding of these mechanisms opens new possibilities for the development of multiple T cell-based combination therapies to improve ICI effectiveness.

Keywords: T-cell infiltration; T-cell priming; cold tumor; immune checkpoint inhibitors; nanomedicine.

Figure 1

Tumor immune phenotypes. Based on the spatial distribution of CD8⁺ T lymphocytes in the tumor microenvironment (TME), a gradient of three immunophenotypes is observed: the immune-desert, immune-excluded and immune-inflamed phenotypes. In the immune-desert phenotype, immune cells are absent from the tumor and its periphery. In the immune-excluded phenotype, immune cells accumulate but do not efficiently infiltrate. In the immune-inflamed phenotype, immune cells infiltrate but their effects are inhibited. Notably, the three different phenotypes have different response rates to immune checkpoint inhibitors.

Figure 2

The tumor-immunity cycle and three immunophenotypes. Antitumor immunity is mediated to a large extent by CD8⁺ T lymphocytes. The tumor-immunity cycle consists of the following steps: (1) tumor antigen release, (2) tumor antigen processing and presentation, (3) T-cell priming and activation, (4) trafficking of T lymphocytes through the bloodstream to tumors, (5) infiltration of T lymphocytes into the tumor parenchyma from the vasculature or tumor periphery, (6) recognition of tumor cells, and (7) cytotoxic T lymphocyte (CTL) destruction of tumor cells by granule exocytosis or through the Fas/FasL pathway. Dead tumor cells release additional antigens, allowing the tumor-immunity cycle to continue. Notably, tumors with the immune-desert phenotype (yellow) cannot pass steps 1-3 due to the absence of T lymphocytes in both the tumor and its margins. Tumors with the immune-excluded phenotype (blue) cannot exceed steps 4-5 due to a lack of T lymphocytes in the tumor bed. Tumors with the immune-inflamed phenotype (red) cannot exceed steps 6-7 due to T-cell exhaustion and checkpoint activation. Adapted with permission from , copyright 2013 Elsevier.

Figure 3

Mechanisms of three distinct tumor phenotypes. Three different phenotypes are associated with specific biological mechanisms. Tumors with the immune-desert phenotype (yellow) may lack T-cell priming due to the absence of tumor antigens, defective antigen processing and presentation machinery, or impaired DC-T-cell interactions. Tumors with the immune-excluded phenotype (blue) may exhibit activation of oncogenic pathways, aberrant chemokines, aberrant vasculature and hypoxia, or an immunosuppressive tumor microenvironment (e.g., stromal barriers). Tumors with the immune-inflamed phenotype (red) can be infiltrated by many immune cells, but these immune cells are suppressed due to checkpoint activation. ADO: adenosine; ATP, adenosine triphosphate; B2M: beta-2-microglobulin; BATF3: basic leucine zipper ATF-like transcription factor 3; CAFs: cancer-associated fibroblasts; CRT, calreticulin; CTLA4, cytotoxic T lymphocyte-associated antigen-4; CXCL: CXC-chemokine ligand; DNMT: DNA methyltransferase; ECM: extracellular matrix; ETBR: endothelin B receptor; EZH2: enhancer of zeste homolog 2; FLT3L: Fms-like tyrosine kinase 3 ligand; GM-CSF: granulocyte-macrophage colony-stimulating factor; HDAC: histone deacetylase; HEV: high endothelial venule; HMGB1: high mobility family protein B1; ICAM: intercellular adhesion molecule; IDO: Indoleamine 2,3-dioxygenase; IFN: interferon; IL: interleukin; MDSC: myeloid-derived suppressor cell; MHC: major histocompatibility complex; PD-1, programmed cell death protein 1; PD-L1, PD-1 ligand; STC1: stanniocalcin 1; TAM: tumor-associated macrophage; TAP: transporter associated with antigen processing; TGFβ: transforming growth factor-β; TIM3, T cell immunoglobulin and mucin domain-containing 3; TLR: Toll‑like receptor; TLS: tertiary lymphoid structure; TME: tumor microenvironment; Treg: T-regulatory cell; VCAM: vascular cell adhesion molecule; VEGF: vascular endothelial growth factor.

Figure 4

Approaches to turn a “cold tumor” into a “hot tumor”. Some representative approaches that lead to increased T-cell infiltration and improved efficacy of immune checkpoint inhibitors are highlighted here. (A) Oncolytic viruses, local thermal ablation therapy (e.g., radiofrequency ablation), chemotherapy, and radiotherapy are all capable of inducing immunogenic cell death (ICD) to promote T-cell priming and activation. Local administration of immune adjuvants such as TLR agonists promotes the activation of dendritic cells (DCs). Epigenetic modification inhibitors can promote T-cell priming by increasing the expression of tumor antigens and by restoring antigen processing and presentation mechanisms. (B) Cancer vaccines and adoptive cellular therapies, such as CAR-T cells, can promote the expansion of tumor-specific T lymphocytes. (C) Intrinsic oncogenic pathway inhibitors, epigenetic modification inhibitors, antiangiogenic therapies, TGFβ inhibitors, and CXCR4 inhibitors promote T-cell trafficking and enable T cells to infiltrate the tumor more effectively.

Figure 5

Improving T-cell infiltration with nanomedicines. Nanomedicines have three different targeting pathways: tumor cells, the TME, and the peripheral immune system. (A) Multiple approaches including photothermal therapy (PTT), photodynamic therapy (PDT), magnetic hyperthermia (MH), and high-intensity focused ultrasound (HIFU) can induce ICD by promoting the release of tumor antigens and damage-associated molecular patterns (DAMPs). The released DAMPs act as adjuvants to enhance the immunogenicity of the tumor and, together with the released tumor antigens, promote dendritic cell (DC) activation and T-cell priming. (B) When targeting the TME, nanomedicines inhibit immunosuppressive cells and immunosuppressive molecules (e.g., TGFβ) and enhance the activity of T cells. (C) When the peripheral immune system is targeted, nanomedicines are engineered to augment tumor antigen presentation and T-cell priming in lymph nodes. Adapted with permission from , copyright 2019 American Chemical Society.

Figure 6

Schematic illustration of pyroptosis and size-transformable nanoparticles. (A) Multiple nanomedicines regulate the expression of caspase proteins that mediate the pyroptosis process. Activated caspases cut gasdermin (GSDM) into two fragments: the C-terminal domain and the N-terminal domain. Following cleavage, the gasdermin-N domains result in cell swelling with big bubbles. Gasdermin-induced pyroptosis results in the release of a massive quantity of proinflammatory molecules and activation of T cells. (B) Use of size-transformable nanoparticles to prolong the circulation time and realize deep penetration.