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Combination cancer immunotherapies tailored to the tumour microenvironment
Abstract
Evidence suggests that cancer immunotherapy will be a major part of the combination treatment plan for many patients with many cancer types in the near future. There are many types of immune processes involving different antitumour and tumour-promoting leucocytes, and tumour cells use many strategies to evade the immune response. The tumour microenvironment can help determine which immune suppressive pathways become activated to restrain antitumour immunity. This includes immune checkpoint receptors on effector T-cells and myeloid cells, and release of inhibitory cytokines and metabolites. Therapeutic approaches that target these pathways, particularly immune-checkpoint receptors, can induce durable antitumour responses in patients with advanced-stage cancers, including melanoma. Nevertheless, many patients do not have a good response to monotherapy approaches and alternative strategies are required to achieve optimal therapeutic benefit. These strategies include eliminating the bulk of tumour cells to provoke tumour-antigen release and antigen-presenting cell (APC) function, using adjuvants to enhance APC function, and using agents that enhance effector-cell activity. In this Review, we discuss the stratification of the tumour microenvironment according to tumour-infiltrating lymphocytes and PD-L1 expression in the tumour, and how this stratification enables the design of optimal combination cancer therapies tailored to target different tumour microenvironments.
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“On the other hand, some positive factors such as immunogenic cancer cell death, immunosupportive cytokines, and professional antigen presentation cells (pAPCs) contribute to immune clearance [21].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [21]
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“During the past decade, immunotherapy, particularly immune checkpoint blockade (ICB), has achieved success in the treatment of multiple malignancies (6).”
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“Stratification of tumor microenvironment according to tumor infiltrating immune cells and PD-L1 expression will enable the development ofmore effective immuno-oncology approaches [33].”
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“Therefore, to enhance the immunotherapy response in “cold” tumors, combinations of multiple treatment strategies have been investigated, including combinations of different immunotherapies [15] and combinations of immunotherapy and other therapeutic strategies such as chemotherapy, radiotherapy and/or targeted therapi…”
BackgroundSurvival-Inferred Fragility Index of Phase 3 Clinical Trials Evaluating Immune Checkpoint Inhibitors
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“Immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) or programmed cell death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) have revolutionized cancer treatment and led to their approval as first-line therapies, either alone or in combination with chemotherapy, for…”
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“Among epigenetic modifiers are DNA methyltransferases, which can induce the re-expression of β2-microglobulin, T-cell-recruiting chemokines and tumourassociated antigens to facilitate the activation of tumour-specific T cells, T-cell trafficking to the tumour and increased tumour immunogenicity.136 In the case of alte…”
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“The addition of immunotherapeutic agents to FOLFIRINOX is also proposed to strengthen and synergistically increase anti-tumor effects [73].”
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Integrated analysis reveals the molecular features of fibrosis in triple-negative breast cancer
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“Recently, three major immune phenotypes have been proposed in cancer, namely, the immune-inflamed, immune-excluded, and immune-desert phenotypes.(41) Given the low expression of coinhibitory molecules in tumors with high fibrosis, highly fibrotic TNBC is more likely to be an immune-excluded cancer type.”
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“Notably, combination systemic therapy was associated with significantly increased IFNγ-producing CD8+ TILs in the metastatic PDAC TME, decreased Tregs, and decreased CTLA-4 expression on CD4+ and CD8+ T-cells when compared to controls.”
BackgroundInfluentialIL-32γ potentiates tumor immunity in melanoma
Gruber, T., Kremenovic, M., Sadozai, H., Rombini, N., Bäriswyl, L., Maibach, F., Modlin, R. L., Gilliet, M. F., von Werdt, D., Hunger, R. E., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.138772 · Cited by 41
“While DC-and macrophage-targeted agents (e.g., anti-CD40 and poly-ICLC) are being tested in clinical trials, none have demonstrated sufficient efficacy to warrant regulatory approval for solid tumors (15, 16).”
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“small number of patients achieve a complete response, but most show incomplete responses without remarkable clinical benefits (Smyth et al., 2016).”
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“RT has also been shown to enhance APC function, overcome T-cell exhaustion, and enhance effector T-cell functions (4,52,53).”
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“Because only a small portion of patients responds to checkpoint inhibitors as monotherapy, there is growing interest in combining other chemotherapies to enhance treatment efficacy (16).”
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“The improved response of combination therapy is likely due to synergistic effects of targeting multiple immune pathways and aiding in the prevention of drug resistance [78].”
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“[5] recently suggested a combination immunotherapy tailored to the TME based on the presence of PD-L1 expression and TILs.”
BackgroundMethodInfluentialNeutrophils Deficient in Innate Suppressor IRAK-M Enhances Anti-tumor Immune Responses
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“Tumor-associated neutrophils may compromise the anti-cancer immune response through expressing co-inhibitory molecules such as programmed death ligand 1 (PD-L1) and suppressing T cell proliferation and activation.(11,12) Clinical studies further reveal that cancer patients may have heterogeneous neutrophil populations…”
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“On one hand, our supramolecular protein chaperone exerted powerful anti-tumor immune activation by enhancing antigen present cells (APCs) function and inducing effector T lymphocytes/macrophages [49-52]; On the other hand, the flurbiprofen-modified D-peptide reduced immune suppression by inhibiting COX-2/PGE2 pathway…”
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Adenosine and adenosine receptors in colorectal cancer
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“A great deal of success has been achieved in the treatment of various malignancies with combination immunotherapy based on ICI [23, 24].”
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“[3] For example, the efficacy of one type of cancer immunotherapy, immune checkpoint blockade antibodies, in patients with breast cancer, which has relatively less TILs (mean percentage of 10%), [4] is far less effective compared to that in patients with melanoma or non-small cell lung carcinoma, characterized as “inf…”
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“therapeutic agents, chemotherapy and/or radiation therapy.(175,271,306-308) Future will tell which (if any) of these”
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“In addition, to improve the efficacy of cancer immunotherapy, the combination of immunotherapy with chemotherapy, radiotherapy, or targeted therapies has been explored [14].”
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“Importantly, individual immunotherapies tailored to optimal pathways have achieved great clinical efficacy in tumor eradication, activation of tumor infiltrating lymphocytes (TILs) and in the function of antigen presenting cells (APCs) [26].”
Background
Metadata
- Authors
- Smyth, M. J., Ngiow, S. F., Ribas, A., & Teng, M. W. L.
- Affiliations
- QIMR Berghofer Medical Research Institute (AU)
- University of California, Los Angeles (US)
- Corresponding author
- Teng, Michele W. L.
- Venue
- Nature Reviews Clinical Oncology
- Published
- 2015-11-24
- Volume
- 13
- Issue
- 3
- Pages
- 143-158
- ISSN
- 1759-4774 (ISSN-L)
- 1759-4782
- OpenAlex
- W2257916459
- Cited by
- 944
- References
- 218
- Citations by year
- 2026: 28 · 2025: 50 · 2024: 71 · 2023: 82 · 2022: 132 · 2021: 102 · 2020: 134 · 2019: 95 · 2018: 99 · 2017: 89 · 2016: 56 · 2015: 3
- FWCI
- 8.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Amgen
- Bristol-Myers Squibb
- Kite Pharma
- National Cancer Institute (R35CA197633)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- cancer immunotherapy, combination therapy, tumor microenvironment, immune evasion, immune checkpoint receptors, PD-L1, tumor-infiltrating lymphocytes, myeloid cells, inhibitory cytokines, antigen-presenting cells, adjuvants, melanoma
- MeSH terms
- Adjuvants, Immunologic, Animals, Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Humans, Immunotherapy, Neoplasms, Signal Transduction, Treatment Outcome, Tumor Escape, Molecular Targeted Therapy, Tumor Microenvironment, B7-H1 Antigen
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