Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Jun;30(6):507-519.
doi: 10.1038/s41422-020-0337-2. Epub 2020 May 28.

The future of cancer immunotherapy: microenvironment-targeting combinations

Yonina R Murciano-Goroff #  1 , Allison Betof Warner #  1   2   3   4 , Jedd D Wolchok  5   6   7   8
Affiliations

The future of cancer immunotherapy: microenvironment-targeting combinations

Yonina R Murciano-Goroff et al. Cell Res. 2020 Jun.

Abstract

Immunotherapy holds the potential to induce durable responses, but only a minority of patients currently respond. The etiologies of primary and secondary resistance to immunotherapy are multifaceted, deriving not only from tumor intrinsic factors, but also from the complex interplay between cancer and its microenvironment. In addressing frontiers in clinical immunotherapy, we describe two categories of approaches to the design of novel drugs and combination therapies: the first involves direct modification of the tumor, while the second indirectly enhances immunogenicity through alteration of the microenvironment. By systematically addressing the factors that mediate resistance, we are able to identify mechanistically-driven novel approaches to improve immunotherapy outcomes.

PubMed Disclaimer

Conflict of interest statement

Y.R.M.-G. has received support for travel, accommodation, and expenses from AstraZeneca. A.B.W. reports honoraria from: LG Chem Life Sciences Innovation Center, Inc. Consulting or advisory roles for: Iovance Biotherapeutics; Nanobiotix. Research funding from: Leap Therapeutics. J.D.W. is a consultant for: Adaptive Biotech; Amgen; Apricity; Arsenal; Ascentage Pharma; Astellas; AstraZeneca; Bayer; Bristol Myers Squibb; Eli Lilly; F Star; Imvaq; Kyowa Hakko Kirin; Merck; Neon Therapeutics; Psioxus; Recepta; Takara Bio; Trieza; Truvax; Serametrix; Surface Oncology; Syndax; Syntalogic. Research support from: Bristol Myers Squibb; AstraZeneca; Sephora. Equity in: Tizona Pharmaceuticals; Adaptive Biotechnologies; Imvaq; Beigene; Linneaus; Arsenal, Apricity.

Figures

Fig. 1
Fig. 1. Schematic diagram of the interaction between indirect modifiers of the tumor microenvironment and direct tumor modifiers.
Direct tumor modifiers act on tumor cells to promote cellular death. These strategies include chemotherapy, radiation therapy, targeted therapies, and epigenetic agents. Indirect modifiers operate predominantly to shift the microenvironment to favor anti-tumor immunity. This can be achieved by enhancing the efficacy or quantity of effector T cells and APCs and/or inhibiting tolerogenic cells such as Tregs and MDSCs. Indirect modulators may also alter the microenvironment through modification of the gut microbiome, the local vasculature, the cytokine milieu, or by altering cellular metabolism, including of amino acids, glucose, and lipids. As depicted, these mechanisms do not operate in isolation, as modification of the microenvironment may enhance direct tumor cell killing and vice versa.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Tang J, et al. Trial watch: The clinical trial landscape for PD1/PDL1 immune checkpoint inhibitors. Nat. Rev. Drug Discov. 2018;17:854–855. - PubMed
    1. Lu J, Lee-Gabel L, Nadeau MC, Ferencz TM, Soefje SA. Clinical evaluation of compounds targeting PD-1/PD-L1 pathway for cancer immunotherapy. J. Oncol. Pharm. Pract. 2015;21:451–467. - PubMed
    1. Yun S, Vincelette ND, Green MR, Wahner Hendrickson AE, Abraham I. Targeting immune checkpoints in unresectable metastatic cutaneous melanoma: a systematic review and meta-analysis of anti-CTLA-4 and anti-PD-1 agents trials. Cancer Med. 2016;5:1481–1491. - PMC - PubMed
    1. Syn NL, Teng MWL, Mok TSK, Soo RA. De-novo and acquired resistance to immune checkpoint targeting. Lancet Oncol. 2017;18:e731–e741. - PubMed
    1. Aguiar PN, Jr., et al. The role of PD-L1 expression as a predictive biomarker in advanced non-small-cell lung cancer: a network meta-analysis. Immunotherapy. 2016;8:479–488. - PubMed

Publication types