Enhancing Innate Immunity in Combination Therapy for Solid Tumors

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Background

The innate immune system contributes to polarizing the tumor microenvironment (TME) in solid cancers – either towards pro- or anti-tumor responses, and therefore represents a broad range of drug targets. Simultaneously, cancer therapeutic regimens that comprise of two or more co-administered therapies have been approved since 2015 and many new combinations are being tested intensively in the clinic because combination approaches are capable of increasing patient response rate and reducing relapse rates. Repolarization, reprogramming, in vivo or ex vivo expansion, depletion, or de novo activation of innate immune responses are being harnessed to (i) directly lyse or inhibit tumor cell growth, (ii) activate other desirable immune responses, and (iii) shape the TME to favor the elimination of tumor cells via different effector mechanisms.

The anti-cancer innate immune response is comprised of acellular and cellular components. Acellular factors associated with the innate immune system include metabolic immunomodulators (e.g. lactic acid, adenosine, oxygenation levels), hormones, cytokines, growth factors, complement and other cytotoxic or inflammatory mediators, which are often soluble but can also be membrane bound. Cellular innate immunity subsets include monocytes, macrophages, myeloid derived suppressor cells (MDSCs), neutrophils, natural killer (NK) cells, and innate lymphoid cells (ILCs). Furthermore, stromal and associated cell types can under some circumstances mediate responses which may be considered to be part of ‘innate’ immunity. In addition to the secretion of effector molecules, the innate immune system mediates or contributes to other processes such as phagocytosis, necrosis (cytotoxicity), apoptosis, autophagy, and NETosis of tumor cells, as well as formation of vasculature, extracellular matrix, and fibrotic tissue, which together creates a distinct TME that can highly influence therapeutic outcomes. Many of these innate cell subsets can be further subdivided based on their functionality, for example, into regulatory innate cells and M2-like macrophages, which are known to limit anti-tumor responses, and thus also represent ideal targets for new therapies.

The scope of the article collection includes fundamental, translational (pre-clinical), and clinical research that sheds light on the cellular or molecular mechanisms involved in innate anti-cancer immunity, in addition to providing hypotheses or evidence for selecting effective therapeutic combinations where one or more of the included therapies modulates innate immunity. The article collection aims to cover different modalities that enhance innate immunity e.g. small molecules or other molecular adjuvants, vaccines, biologics, and cellular therapies, that are intended to be used in combination with other immune-based therapies (immune checkpoint blockade antibodies, CAR-T cells, TIL therapy, vaccines) or conventional cancer treatments (radiotherapy, chemotherapy, and targeted therapies). Specific topics for the article collection, include, but are not limited to (i) innate immunotherapy that enhances other immune-targeting therapies, (ii) innate immunotherapy in combination with conventional cancer therapies, (iii) emerging drug targets and cutting-edge methodologies in the innate immune system, and (iv) clinical advances and state of the art for combination cancer therapies. The article types recommended for this collection include Original Research, Systematic Review, Review, or Mini Review, Data Report, Brief Research Report, General Commentary, Opinion, and Editorials, Methods, Hypothesis and Theory, Clinical Trials, Case Reports, and Perspectives.

Topic Editor David Pejoski is the founder and CEO of Adoram Therapeutics. The other Topic Editors declare no competing interests with regard to the Research Topic subject.

Keywords: Innate Immunity, Combination Therapy, Solid Tumors

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