The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications

Abstract

Immunotherapy has revolutionized cancer treatment and rejuvenated the field of tumor immunology. Several types of immunotherapy, including adoptive cell transfer (ACT) and immune checkpoint inhibitors (ICIs), have obtained durable clinical responses, but their efficacies vary, and only subsets of cancer patients can benefit from them. Immune infiltrates in the tumor microenvironment (TME) have been shown to play a key role in tumor development and will affect the clinical outcomes of cancer patients. Comprehensive profiling of tumor-infiltrating immune cells would shed light on the mechanisms of cancer-immune evasion, thus providing opportunities for the development of novel therapeutic strategies. However, the highly heterogeneous and dynamic nature of the TME impedes the precise dissection of intratumoral immune cells. With recent advances in single-cell technologies such as single-cell RNA sequencing (scRNA-seq) and mass cytometry, systematic interrogation of the TME is feasible and will provide insights into the functional diversities of tumor-infiltrating immune cells. In this review, we outline the recent progress in cancer immunotherapy, particularly by focusing on landmark studies and the recent single-cell characterization of tumor-associated immune cells, and we summarize the phenotypic diversities of intratumoral immune cells and their connections with cancer immunotherapy. We believe such a review could strengthen our understanding of the progress in cancer immunotherapy, facilitate the elucidation of immune cell modulation in tumor progression, and thus guide the development of novel immunotherapies for cancer treatment.

Keywords: Immunotherapy; Phenotypic diversities; Single-cell technologies; Tumor microenvironment; Tumor-infiltrating immune cells.

Fig. 1

The major categories of immunotherapy. Different forms of cancer immunotherapy, including oncolytic virus therapies, cancer vaccines, cytokine therapies, adoptive cell transfer, and immune checkpoint inhibitors, have evolved and shown promise in clinical practice. The basic principles of each strategy and the corresponding cellular and molecular underpinnings involved in each step are depicted. DCs dendritic cells, NK natural killer, TCR T-cell receptor, CAT-T chimeric antigen receptor T-cell

Fig. 2

Single-cell profiling strategies and single-cell studies performed in different cancer types. a The workflow of single-cell technologies, including scRNA-seq and CyTOF. For scRNA-seq, plate-based and droplet-based strategies are commonly used for in-depth or large-scale analyses. b The summary of current single-cell-based studies for the dissection of immune infiltrates in various tissues and cancer types. Tech technology, FACS fluorescence-activated cell sorting, T tumor, N adjacent normal or healthy tissues, P peripheral blood, Other cells, nonimmune cells, including malignant cells and stroma cells, scTCR single-cell TCR information, BCC basal cell carcinoma, SCC squamous cell carcinoma, NSCLC non-small cell lung cancer, RCC renal cell carcinoma, ccRCC clear cell renal cell carcinoma, CRC colorectal cancer, BC breast cancer, HCC hepatocellular carcinoma, HNSCC head and neck squamous cell carcinoma, Endo AD endometrial adenocarcinoma

Fig. 3

Functional properties and dynamic changes of immune cells in the tumor microenvironment. T cells in peripheral blood infiltrate into tumors and undergo functional state transitions, possibly driven by the immunosuppressive microenvironment. Naive CD8 T cells or CD4 T_H cells differentiate into transitional states and finally reach exhausted states, while resting Tregs transit into suppressive states in tumors.^, Such state transitions result in a reduction of effector T cells yet an accumulation of exhausted T cells and suppressive Tregs, both of which are proven to be proliferating and highly clonally expanded in the TME.^, Myeloid cells in blood are mainly monocytes, including CD14⁺ and CD16⁺ subsets, while these cells tend to differentiate into macrophages and DCs in tumors.^, The TME sculpts them to harbor immunosuppressive phenotypes, resulting in an accumulation of suppressive TAMs and cDC2s but a reduction of CD16⁺ monocytes and cDC1s.^, In addition, single-cell interrogation facilitates the identification of novel subsets of cDCs and TAMs in the TME and reveals that TAM subtypes tend to coexpress M1 and M2 signatures, thus inconsistent with the polarization models.^,, NK cells exert cytotoxic functions with perforin and granzymes when activated by the integrated signals of activating and inhibitory receptors,^– yet they show reduced cell numbers, impaired cytotoxic function and an impeded orchestrating effect for immune responses exemplified by the hampered cDC1 recruitment in the TME.^, The functional defects of NK cells are possibly driven by tumor cells through secreting immunosuppressive factors and expressing ligands of inhibitory receptors while decreasing the expression of ligands of activating receptors to hinder NK activation.^,, B cells play important roles in antitumor immunity and ICI treatment, as B cells and TLSs, containing aggregates of immune cells, including T cells, B cells and FDCs, are found to mediate improved responses to ICIs, the mechanism of which involves the activation of T_FH and B cells.^,, The activated B cells can differentiate not only into plasma B cells to produce antibodies to clear cancer cells but also into active T-cell-mediated immune responses by presenting antigens to CD4 T_H cells that could promote the activation of CD8 T cells. T_N cell naive T-cell, T_CM cell central memory T-cell, T_EM cell effector memory T-cell, T_H cell T helper cell, T_FH cell T follicular helper cell, T_EFF cell effector T-cell, T_EX cell exhausted T-cell, Tregs regulatory T cells, TAMs tumor-associated macrophages, DCs dendritic cells, cDC classical dendritic cell, FDC follicular dendritic cell, GC germinal center, TLS tertiary lymphatic structure, ICIs immune checkpoint inhibitors, TME tumor microenvironment, NK natural killer, APCs antigen-presenting cells, HLA human leukocyte antigen, Mye myeloid cell