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

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

Immunotherapy has revolutionized cancer treatment, but efficacy remains limited in most clinical settings. Cancer is a systemic disease that induces many functional and compositional changes to the immune system as a whole. Immunity is regulated by interactions of diverse cell lineages across tissues. Therefore, an improved understanding of tumour immunology must assess the systemic immune landscape beyond the tumour microenvironment (TME). Importantly, the peripheral immune system is required to drive effective natural and therapeutically induced antitumour immune responses. In fact, emerging evidence suggests that immunotherapy drives new immune responses rather than the reinvigoration of pre-existing immune responses. However, new immune responses in individuals burdened with tumours are compromised even beyond the TME. Herein, we aim to comprehensively outline the current knowledge of systemic immunity in cancer.

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Systemic immunity in cancer

Developmental Relationships of Four Exhausted CD8+ T Cell Subsets Reveals Underlying Transcriptional and Epigenetic Landscape Control Mechanisms

Transcription factors define tissue T cells The immune system fights microbial invaders by maintaining multiple lines of defense. For instance, specialized memory T cells [resident memory T cells (Trms)] colonize portals of pathogen entry, such as the skin, lung, and gut, to quickly halt reinfections. Mackay et al. now report that in mice, Trms as well as other tissue-dwelling lymphocyte populations such as natural killer cells share a common transcriptional program driven by the related transcription factors Hobit and Blimp1. Tissue residency and retention of lymphocytes require expression of Hobit and Blimp1, which, among other functions, suppress genes that promote tissue exit. Science, this issue p. 459 Tissue-dwelling lymphocyte populations share a common transcriptional signature. Tissue-resident memory T (Trm) cells permanently localize to portals of pathogen entry, where they provide immediate protection against reinfection. To enforce tissue retention, Trm cells up-regulate CD69 and down-regulate molecules associated with tissue egress; however, a Trm-specific transcriptional regulator has not been identified. Here, we show that the transcription factor Hobit is specifically up-regulated in Trm cells and, together with related Blimp1, mediates the development of Trm cells in skin, gut, liver, and kidney in mice. The Hobit-Blimp1 transcriptional module is also required for other populations of tissue-resident lymphocytes, including natural killer T (NKT) cells and liver-resident NK cells, all of which share a common transcriptional program. Our results identify Hobit and Blimp1 as central regulators of this universal program that instructs tissue retention in diverse tissue-resident lymphocyte populations.

Hobit and Blimp1 instruct a universal transcriptional program of tissue-residency in lymphocytes

Tumor cells constantly interact with their microenvironment, which comprises a variety of immune cells together with endothelial cells and fibroblasts. The composition of the tumor microenvironment (TME) has been shown to influence response to immune checkpoint blockade (ICB). ICB takes advantage of immune cell infiltration in the tumor to reinvigorate an efficacious antitumoral immune response. In addition to tumor cell intrinsic biomarkers, increasing data pinpoint the importance of the TME in guiding patient selection and combination therapies. Here, we review recent efforts in determining how various components of the TME can influence response and resistance to ICB. Although a large body of evidence points to the extent and functional orientation of the T cell infiltrate as important in therapy response, recent studies also confirm a role for other components of the TME, such as B cells, myeloid lineage cells, cancer-associated fibroblasts, and vasculature. If the ultimate goal of curative cancer therapies is to induce a long-term memory T cell response, the other components of the TME may positively or negatively modulate the induction of efficient antitumor immunity. The emergence of novel high-throughput methods for analyzing the TME, including transcriptomics, has allowed tremendous developments in the field, with the expansion of patient cohorts, and the identification of TME-based markers of therapy response. Together, these studies open the possibility of including TME-based markers for selecting patients that are likely to respond to specific therapies, and pave the way to personalized medicine in oncology.

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The Tumor Microenvironment in the Response to Immune Checkpoint Blockade Therapies.

Despite the resounding clinical success in cancer treatment of antibodies that block the interaction of PD1 with its ligand PDL11, the mechanisms involved remain unknown. A major limitation to understanding the origin and fate of T cells in tumour immunity is the lack of quantitative information on the distribution of individual clonotypes of T cells in patients with cancer. Here, by performing deep single-cell sequencing of RNA and T cell receptors in patients with different types of cancer, we survey the profiles of various populations of T cells and T cell receptors in tumours, normal adjacent tissue, and peripheral blood. We find clear evidence of clonotypic expansion of effector-like T cells not only within the tumour but also in normal adjacent tissue. Patients with gene signatures of such clonotypic expansion respond best to anti-PDL1 therapy. Notably, expanded clonotypes found in the tumour and normal adjacent tissue can also typically be detected in peripheral blood, which suggests a convenient approach to patient identification. Analyses of our data together with several external datasets suggest that intratumoural T cells, especially in responsive patients, are replenished with fresh, non-exhausted replacement cells from sites outside the tumour, suggesting continued activity of the cancer immunity cycle in these patients, the acceleration of which may be associated with clinical response. Large-scale single-cell sequencing of RNA and T cell receptors in samples from patients with cancer shows clonotypic expansion of effector-like T cells not only in tumour tissue but also in normal adjacent tissues and peripheral blood, which associates with clinical response to cancer immunotherapy.

Ivette Estay

Papers

Peripheral T cell expansion predicts tumour infiltration and clinical response