Cancer-induced heterogeneous immunosuppressive tumor microenvironments and their personalized modulation.

Although recent cancer immunotherapy strategies, including immune-checkpoint blockade (i.e. blocking PD-1, PD-L1 or CTLA-4), have shown durable clinical effects in some (but not all) patients with various advanced cancers, further understanding of human immunopathology, particularly in tumor microenvironments, is essential to improve this type of therapy. The major hurdle for immunotherapy is the immunosuppression that is found in cancer patients. There are two types of immunosuppression: one is induced by gene alterations in cancer; the other is local adaptive immunosuppression, triggered by tumor-specific T cells in tumors. The former is caused by multiple mechanisms via various immunosuppressive molecules and via cells triggered by gene alterations, including activated oncogenes, in cancer cells. The various immunosuppressive mechanisms involve signaling cascades that vary among cancer types, subsets within cancer types and individual cancers. Therefore, personalized immune-interventions are necessary to appropriately target oncogene-induced signaling that modulates anti-cancer immune responses, on the basis of genetic and immunological analysis of each patient. Further understanding of human cancer immunopathology may lead to real improvement of current cancer immunotherapies.

Yaguchi T ，Kawakami Y 《-》

Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors.

Inhibition of immune regulatory checkpoints, such as CTLA-4 and the PD-1-PD-L1 axis, is at the forefront of immunotherapy for cancers of various histological types. However, such immunotherapies fail to control neoplasia in a significant proportion of patients. Here, we review how a range of cancer-cell-autonomous cues, tumor-microenvironmental factors, and host-related influences might account for the heterogeneous responses and failures often encountered during therapies using immune-checkpoint blockade. Furthermore, we describe the emerging evidence of how the strong interrelationship between the immune system and the host microbiota can determine responses to cancer therapies, and we introduce a concept by which prior or concomitant modulation of the gut microbiome could optimize therapeutic outcomes upon immune-checkpoint blockade.

Pitt JM ，Vétizou M ，Daillère R ，Roberti MP ，Yamazaki T ，Routy B ，Lepage P ，Boneca IG ，Chamaillard M ，Kroemer G ，Zitvogel L ... -  《-》

Immune checkpoint inhibitors in cancer therapy: a focus on T-regulatory cells.

Regulatory T cells (Tregs) play essential roles in immune homeostasis; however, their role in tumor microenvironment (TME) is not completely evident. Several studies reported that infiltration of Tregs into various tumor tissues promotes tumor progression by limiting antitumor immunity and supporting tumor immune evasion. Furthermore, in TME, Tregs include heterogeneous subsets of cells expressing different immunosuppressive molecules favoring tumor progression. For an effective cancer therapy, it is critical to understand the Treg heterogeneity and biology in the TME. Recent studies have shown that immune checkpoint molecules promote cancer progression through various antitumor inhibitory mechanisms. Recent advances in cancer immunotherapy have shown the promising potentials of immune checkpoint inhibitors (ICIs) in inducing antitumor immune responses and clinical benefits in patients with cancer at late stages. Most studies revealed the effect of ICIs on T effector cells, and little is known about their effect on Tregs. In this review, we highlight the effects of the ICIs, including anti-CTLA-4, anti-PD-1/PD-L1, anti-LAG-3, anti-TIM-3, and anti-TIGIT, on tumor-infiltrating and peripheral Tregs to elicit effector T-cell functions against tumors. Additionally, we discuss how ICIs may target Tregs for cancer immunotherapy.

Sasidharan Nair V ，Elkord E 《-》

New insight into cancer immunotherapy.

A key point for maintenance of the immune system homeostasis is the balance between the capacity to recognize and fight exogenous molecules and the capacity to avoid auto reactivity. The disruption of this balance induces the progression of several immune diseases such as autoimmune diseases, allergies, infections or cancer. A promising therapeutic approach to treat these diseases is immunotherapy. In cancer, both active and passive immunotherapies have been tested with promising results, such as the blocking of immunological checkpoints like CTLA-4 and PD-1. These treatments, in the market since a few years ago, aim to redirect the patient's immunological response by inhibiting the induction of regulatory T cells, both in the priming and effector phases. This strategy sheds light on the immunological mechanisms that control the regulatory response mediated by T cells and opens new lines of research into other immunological diseases such as allergy, in which the induction of a regulatory response is necessary to avoid allergic progression and which is the main objective of allergen-specific immunotherapies available today.

Escribese MM ，Barber D 《-》

Active Immunotherapy of Cancer.

Chodon T ，Koya RC ，Odunsi K 《-》