Roles for Innate Immunity in Combination Immunotherapies

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Abstract

Immunity to infectious agents involves a coordinated response of innate and adaptive immune cells working in concert, with many feed-forward and regulatory interactions between both arms of the immune system. In contrast, many therapeutic strategies to augment immunity against tumors have focused predominantly on stimulation of adaptive immunity. However, a growing appreciation of the potential contributions of innate immune effectors to antitumor immunity, especially in the context of combination immunotherapy, is leading to novel strategies to elicit a more integrated immune response against cancer. Here we review antitumor activities of innate immune cells, mechanisms of their synergy with adaptive immune responses against tumors, and discuss recent studies highlighting the potential of combination therapies recruiting both innate and adaptive immune effectors to eradicate established tumors. Cancer Res; 77(19); 5215–21. ©2017 AACR.



https://cancerres.aacrjournals.org/content/77/19/5215

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Innate immune recognition of cancer

Abstract

The observation that a subset of cancer patients show evidence for spontaneous CD8+ T cell priming against tumor-associated antigens has generated renewed interest in the innate immune pathways that might serve as a bridge to an adaptive immune response to tumors. Manipulation of this endogenous T cell response with therapeutic intent-for example, using blocking antibodies inhibiting PD-1/PD-L1 (programmed death-1/programmed death ligand 1) interactions-is showing impressive clinical results. As such, understanding the innate immune mechanisms that enable this T cell response has important clinical relevance. Defined innate immune interactions in the cancer context include recognition by innate cell populations (NK cells, NKT cells, and γδ T cells) and also by dendritic cells and macrophages in response to damage-associated molecular patterns (DAMPs). Recent evidence has indicated that the major DAMP driving host antitumor immune responses is tumor-derived DNA, sensed by the stimulator of interferon gene (STING) pathway and driving type I IFN production. A deeper knowledge of the clinically relevant innate immune pathways involved in the recognition of tumors is leading toward new therapeutic strategies for cancer treatment.




https://www.ncbi.nlm.nih.gov/pubmed/256 ... t=Abstract

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Cont..

Introduction
The heterogeneity of human cancers combined with the diversity of mechanisms acting in concert within established tumors to suppress the immune response make it unlikely that any single-agent immunotherapy will elicit meaningful tumor regression in a majority of patients—an expectation that has prompted the search for safe and efficacious combination therapies. The countless number of potential combination therapy permutations possible even within the existing pool of immunotherapy drugs in early clinical testing motivates the need for rational approaches to identify promising combination therapies. Progress in understanding the tumor microenvironment and antitumor immunity has led to the proposal that several functional steps are required for the immune response to eliminate established tumors, including blockade of immunosuppression, promotion of immune infiltration, induction of immunogenic tumor cell death, activation of antigen-presenting cells, and enhancement of effector cell activity (1–3). Identification of these target functional requirements sets the stage for designing combination treatments that address distinct barriers to tumor rejection.
Many studies have focused on combination therapies that promote complementary features of T-cell activity (e.g., treatment with vaccines, antibodies blocking inhibitory receptors, and antibodies agonizing costimulatory receptors) or that synthetically substitute for B cells (antitumor mAbs). However, natural immune responses are never based solely in adaptive immunity; innate immune cells play an important role in complementing the effector activities of CD4+ and CD8+ T cells, and provide unique pathways to bolster an ongoing adaptive response. In this brief review, we discuss pertinent features of innate responses to tumors, and examine findings from recent combination immunotherapy studies that have revealed unexpected important roles for innate immunity in successful antitumor therapies.

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Key Points
Following immunization, CD4+ T cells promote the induction of a robust primary CD8+ T cell response through numerous mechanisms, including licensing of dendritic cells (DCs) and promoting the interaction between DCs and CD8+ T cells.

CD4+ T cells regulate the secondary responsiveness of CD8+ T cells during immunization through suppression of TNF-related apoptosis-inducing ligand (TRAIL) through a process dependent on licensing of DCs to produce interleukin-15 (IL-15) and autocrine secretion of IL-2 by CD8+ T cells.

Following infection, CD4+ T cell help is necessary for the induction of a memory CD8+ T cell pool capable of mediating protective immunity but is largely dispensable for a robust primary response.

Regulatory T (TReg) cells act during the resolution phase of infection to protect CD8+ T cells from inflammatory signals and promote the survival of a CD8+ T cell pool capable of robustly expanding upon secondary infection.

CD4+ T cell help promotes the induction of tissue-resident memory CD8+ T cells during mucosal infection through guidance of CD8+ T cells into a microenvironment where they can become exposed to the signals necessary for their continued maintenance within the tissue.

During chronic infection, effector CD4+ T cells support the maintenance of functional CD8+ T cells through secretion of IL-21, whereas TReg cells dampen the CD8+ T cell response through suppression of DCs.

Abstract
Following infection, T cells differentiate into a heterogeneous population of effector T cells that can mediate pathogen clearance. A subset of these effector T cells possesses the ability to survive long term and mature into memory T cells that can provide long-term immunity. Understanding the signals that regulate the development of memory T cells is crucial to efforts to design vaccines capable of eliciting T cell-based immunity. CD4+ T cells are essential in the formation of protective memory CD8+ T cells following infection or immunization. However, until recently, the mechanisms by which CD4+ T cells act to support memory CD8+ T cell development following infection were unclear. Here, we discuss recent studies that provide insight into the multifaceted role of CD4+ T cells in the regulation of memory CD8+ T cell differentiation.

https://www.nature.com/articles/nri.2015.10

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The Innate vs. Adaptive Immune Response
The first line of defense against non-self pathogens is the innate, or non-specific, immune response. The innate immune response consists of physical, chemical and cellular defenses against pathogens. The main purpose of the innate immune response is to immediately prevent the spread and movement of foreign pathogens throughout the body.

The second line of defense against non-self pathogens is called adaptive immune response. Adaptive immunity is also referred to as acquired immunity or specific immunity and is only found in vertebrates. The adaptive immune response is specific to the pathogen presented. The adaptive immune response is meant to attack non-self pathogens but can sometimes make errors and attack itself. When this happens, autoimmune diseases can develop (e.g., lupus, rheumatoid arthritis).”quote

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innate
existing in, belonging to, or determined by factors present in an individual from birth : native, inborn. innate behavior. 2. : belonging to the essential nature of something : inherent.

Lymphatic or Hematogenous Dissemination: How Does a Metastatic Tumor Cell Decide?

http://www.cureasps.org/forum/viewtopic ... 8688#p8688