Abstract
Immunotherapy has emerged as a promising strategy for boosting antitumoral immunity. Blockade of immune checkpoints (ICs), which regulate the activity of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells has proven clinical benefits. Antibodies targeting CTLA-4, PD-1, and PD-L1 are IC-blockade drugs approved for the treatment of various solid and hematological malignancies. However, a large subset of patients does not respond to current anti-IC immunotherapy. An integrative understanding of tumor-immune infiltrate, and IC expression and function in immune cell populations is fundamental to the design of effective therapies. The simultaneous blockade of newly identified ICs, as well as of previously described ICs, could improve antitumor response. We review the potential for novel combinatory blockade strategies as antitumoral therapy, and their effects on immune cells expressing the targeted ICs. Preclinical evidence and clinical trials involving the blockade of the various ICs are reported. We finally discuss the rationale of IC co-blockade strategy with respect to its downstream signaling in order to improve effective antitumoral immunity and prevent an increased risk of immune-related adverse events (irAEs).
Highlights
Effector cells: cytotoxic T lymphocytes and natural killer cells Cytotoxic T lymphocytes (CTLs) and NK cells are the two major immune populations that are able to eliminate malignant cells
The continuous interaction between immune checkpoints (ICs) ligands and their respective IC receptors expressed by CTLs and NK, help produce a dysfunctional state in these immune cells known as exhaustion
CTLs participate in the adaptive immune response while NK cells are part of the innate immune system
Summary
Tumor growth involves a complex interplay between tumor, immune, and stromal cells, and extracellular matrix components. Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells are immune cell populations responsible for immunosurveillance and, when required, for eliminating target cells. The continuous interaction between IC ligands and their respective IC receptors expressed by CTLs and NK, help produce a dysfunctional state in these immune cells known as exhaustion. Tumors avoid antitumoral immunity by upregulating the expression of IC ligands and recruiting immunosuppressive cells, which give rise to an immunosuppressive tumor microenvironment (TME). Pharmacological blockade of the interaction between ICs and their ligands with IC inhibitors has been identified as a promising strategy for restoring immune cytotoxic activity [5]. The IC receptors expressed by NK and T cells can be expressed by other immune cell populations, and their blockade may modulate the function of those populations. We analyze the antitumoral activity of IC blockade therapies, as single agents or in combination, for cancer treatment
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