References for this Review were identified in PubMed using the search terms “non-immunogenic”, “cold tumours”, and “immunotherapy”, plus the respective mechanisms discussed in each chapter. Only papers published in English between Jan 1, 2014, and Sept 30, 2019, were reviewed. The final reference list was generated on the basis of originality and relevance to the broad scope of this Review.
ReviewTurning up the heat on non-immunoreactive tumours: opportunities for clinical development
Introduction
Cancer treatment has evolved in the past 10 years from a strategy mainly focused on targeting tumour cells, to a broader therapeutic strategy encompassing targeted activation of immune cells to help fight tumour cells. Notable advances have been made in cancer immunotherapy, with the development of immune checkpoint inhibitors (ICIs) approved to treat various tumour types. However, despite their efficacy, many patients go on to have progressive disease. Initial response likely depends on the tumour immune phenotype at baseline.1 Consequently, tumour immune classification systems (based on the type of immune-cell infiltrate, density, and location) have been proposed to characterise the immunological tumour status and predicted responses to ICIs.1, 2 These classifications offer clues for the development of therapeutic approaches to overcome primary therapeutic failures.
In this Review, we outline the main tumour immune phenotypes that have been described in the literature thus far, and the underlying tumour features that probably affect the efficacy of immunotherapy. We then offer a conceptual therapeutic framework based on five main strategies that aim to enhance ICI efficacy. These include increasing inflammation in the tumour microenvironment of non-inflamed tumours; neutralising immunosuppressive factors at the tumour site; normalising tumour vasculature; targeting tumour-cell-intrinsic pathways; and increasing tumour-specific T cells. We recognise that, as with any tumour classification, the one offered in this Review might be an oversimplification, considering the complex interplay between the tumour and the immune system. Furthermore, we recognise that the conceptual framework in which we organised our thinking is, by default, arbitrary, given that the proposed therapeutic strategies can be approached from different perspectives. Moreover, although at the surface these therapeutic strategies could appear orthogonal, the strategies discussed can induce multiple effects on immune cells, as well as tumour cells. Thus, individual therapeutic interventions can in fact have overlapping mechanisms of action and thus be assigned to more than one of the main strategies listed above. Understanding these limitations, we will attempt to provide a concise overview of the field based on our current understanding of the mechanisms underlying T-cell exclusion and immune desertification of tumours, and available opportunities for rational interventions, with the aim of reprogramming tumours to enhance T-cell infiltration, engraftment, and function, to ultimately improve patient response to ICIs.
Section snippets
Immune phenotypes determine immunotherapy outcomes
Tumours can be spontaneously populated by T cells, which can succeed in infiltrating tumour nests.3 Careful assessment of tumour-infiltrating lymphocytes (TILs) has helped distinguish three dominant immune phenotypes: immune-inflamed, immune-excluded, and immune-desert, which roughly correlate with response to PD-1 blockade.2 Tumours with an immune-inflamed phenotype, also known as hot tumours, are characterised by an increased infiltration of CD4 T cells and CD8 T cells to the stroma, the
Therapeutic strategies for non-immunoreactive tumours
During the past 5 years, emphasis on tumour heterogeneity has revealed that classifying tumours on the basis of their immune phenotype is an over-simplification.2 Tumours might have areas of immune cell infiltration next to areas of immune exclusion or desertification, indicating that tumour cells and immune infiltrate coevolve.16, 17 Nevertheless, this classification approach offers a convenient model to interpret responses to immunotherapy and elaborate rational therapeutic strategies (figure
Conclusion
Advances in our understanding of mechanisms at the tumour microenvironment and an ever-expanding therapeutic toolbox have led to an unprecedented increase in clinical trial opportunities in immuno-oncology. Therefore, investigators and clinicians are faced with numerous possibilities of potential interventions to develop combinatorial approaches for addressing the intrinsic immune resistance of cold tumours. Increasingly, opportunities for personalised treatments will become available to the
Search strategy and selection criteria
References (104)
- et al.
Cooperation between constitutive and inducible chemokines enables T cell engraftment and immune attack in solid tumors
Cancer Cell
(2019) - et al.
Primary, adaptive, and acquired resistance to cancer immunotherapy
Cell
(2017) - et al.
A cancer cell program promotes T cell exclusion and resistance to checkpoint blockade
Cell
(2018) - et al.
Pattern recognition receptors: immune targets to enhance cancer immunotherapy
Ann Oncol
(2017) - et al.
Rationale for stimulator of interferon genes-targeted cancer immunotherapy
Eur J Cancer
(2017) - et al.
Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy
Cell
(2017) - et al.
Combined locoregional-immunotherapy for liver cancer
J Hepatol
(2019) - et al.
Interventional therapy combined with immune checkpoint inhibitors: emerging opportunities for cancer treatment in the era of immunotherapy
Cancer Treat Rev
(2019) - et al.
Enhancement of the antitumor properties of interleukin-2 by its targeted delivery to the tumor blood vessel extracellular matrix
Blood
(2002) - et al.
Low-dose irradiation programs macrophage differentiation to an iNOS+/M1 phenotype that orchestrates effective T cell immunotherapy
Cancer Cell
(2013)
Radiation enhances regulatory T cell representation
Int J Radiat Oncol Biol Phys
[177Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study
Lancet Oncol
Inflammatory reprogramming with IDO1 inhibitors: turning immunologically unresponsive ‘cold’ tumors ‘hot’
Trends Cancer
Epacadostat (E) plus pembrolizumab (P) versus pembrolizumab alone in patients (pts) with unresectable or metastatic melanoma: results of the phase 3 ECHO-301/KEYNOTE-252 study
Proc Am Soc Clin Oncol
Reprogramming tumor blood vessels for enhancing immunotherapy
Trends Cancer
Targeting Wnt/β-catenin signaling for cancer immunotherapy
Trends Pharmacol Sci
Oncogenic activation of the PI3K/Akt pathway promotes cellular glucose uptake by downregulating the expression of thioredoxin-interacting protein
Cell Signal
MYC: master regulator of immune privilege
Trends Immunol
Metabolic reprogramming of immune cells in cancer progression
Immunity
Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial
Lancet Oncol
The cancer epigenome: exploiting its vulnerabilities for immunotherapy
Trends Cell Biol
HDAC inhibitors as epigenetic regulators for cancer immunotherapy
Int J Biochem Cell Biol
Efficacy of adoptive therapy with tumor-infiltrating lymphocytes and recombinant interleukin-2 in advanced cutaneous melanoma: a systematic review and meta-analysis
Ann Oncol
The where, the when, and the how of immune monitoring for cancer immunotherapies in the era of checkpoint inhibition
Clin Cancer Res
Elements of cancer immunity and the cancer-immune set point
Nature
Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer
N Engl J Med
PD-1 blockade induces responses by inhibiting adaptive immune resistance
Nature
Density of immunogenic antigens does not explain the presence or absence of the T-cell-inflamed tumor microenvironment in melanoma
Proc Natl Acad Sci USA
Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer
Science
Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade
Science
Immune checkpoint inhibitors: recent progress and potential biomarkers
Exp Mol Med
T cell-inflamed versus non-T cell-inflamed tumors: a conceptual framework for cancer immunotherapy drug development and combination therapy selection
Cancer Immunol Res
Role of galectins in tumors and in clinical immunotherapy
Int J Mol Sci
Competition for nutrients and its role in controlling immune responses
Nat Commun
Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy
Nat Med
Mutations associated with acquired resistance to PD-1 blockade in melanoma
N Engl J Med
Clonal status of actionable driver events and the timing of mutational processes in cancer evolution
Sci Transl Med
Agnostic-histology approval of new drugs in oncology: are we already there?
Clin Cancer Res
The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy
Nat Rev Cancer
The promise of neoadjuvant immunotherapy and surgery for cancer treatment
Clin Cancer Res
Tolerance, danger, and the extended family
Annu Rev Immunol
Harnessing the immune system to fight cancer with Toll-like receptor and RIG-I-like receptor agonists
Pharmacol Res
SD-101 in Combination with pembrolizumab in advanced melanoma: results of a phase Ib, multicenter study
Cancer Discov
STING agonist inflames the pancreatic cancer immune microenvironment and reduces tumor burden in mouse models
J Immunother Cancer
Established T cell-inflamed tumors rejected after adaptive resistance was reversed by combination sting activation and PD-1 pathway blockade
Cancer Immunol Res
Integrating oncolytic viruses in combination cancer immunotherapy
Nat Rev Immunol
Oncolytic viruses as engineering platforms for combination immunotherapy
Nat Rev Cancer
Tumor microenvironment remodeling by intratumoral oncolytic vaccinia virus enhances the efficacy of immune-checkpoint blockade
Clin Cancer Res
Immunotherapy and the interventional oncologist: challenges and opportunities-a society of interventional oncology white paper
Radiology
Bispecific antibodies: a mechanistic review of the pipeline
Nat Rev Drug Discov
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2023, Fundamental ResearchCitation Excerpt :Primary resistance to tumor vaccines is prominently associated with low tumor-infiltrating immune cells, so-called cold tumors. Great hopes are placed on turning cold tumors into T-cell-infiltrated hot tumors by augmenting immunostimulation and abrogating immunosuppression at the tumor site [85]. Vaccination is capable of reversing immunosuppression in the TME, which greatly enhances therapeutic potency [86] (Fig. 2).