We identified references for this Review through searches of PubMed between Sept 16, 2016, and May 10, 2017. We searched for articles published between Jan 1, 2008, and May 1, 2017, using the search terms “resistance”, “relapse”, “recurrence”, “cancer immunotherapy”, “checkpoint blockade”, “anti-PD-1”, “anti-PD-L1”, and “anti-CTLA-4”. We focused on the mechanistic aspects of resistance to immune checkpoint targeting and potential strategies to reverse resistance, and reviewed both preclinical
ReviewDe-novo and acquired resistance to immune checkpoint targeting
Introduction
Since the beginning of the 20th century, when Paul Ehrlich1 formulated his enduring immune surveillance hypothesis, which proposed the immune system was centrally important for eradication of the overwhelming frequency of clinically undetectable carcinomas, research on cancer and immunity has focused on how a subpopulation of malignant cells eventually escape immunological control to establish macroscopic and clinically manifesting colonies. A direct consequence of these conceptual foundations was the premise that effective cancer treatment hinges on our capacity to block—or even reverse—immune-escape mechanisms. This field has been validated by seminal work from Leach and colleagues,2 who showed that blockade of T-cell suppressive pathways could unchain T-cell-dependent rejection of pre-established cancers in immunocompetent mouse models.
Immune checkpoints are orchestrated by a set of costimulatory and inhibitory molecules, which regulate the activation and effector functions of T lymphocytes. These regulatory circuits enable self-tolerance under normal physiological contexts but frequently become coopted in malignancy. Accordingly, immune checkpoint blockers—such as ipilimumab (anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA-4]), pembrolizumab and nivolumab (anti-programmed cell death protein-1 [PD-1]), and atezolizumab, durvalumab, and avelumab (anti-programmed cell death ligand-1 [PD-L1])—have shown activity in clinical trials, and are gaining approval for an expanding array of indications. These indications include metastatic melanoma,3, 4, 5, 6, 7, 8, 9, 10 advanced non-small-cell lung cancer,11, 12, 13, 14 renal cell carcinoma,15 classic Hodgkin's lymphoma,16, 17, 18, 19 urothelial cancers,20, 21, 22, 23 squamous cell cancer of the head and neck,24, 25, 26, 27 Merkel cell carcinoma,28, 29 and, more recently, solid tumours that show microsatellite instability (MSI-H) and mismatch repair deficiency.25, 30, 31, 32, 33
Despite the transformative potential of immune checkpoint blockers, upfront clinical benefits in approved indications are not universal. For patients with either metastatic melanoma or non-small-cell lung cancer for instance, 19–45% of unselected, previously treated patients,3, 4, 5, 14 or 40–45% of patients with PD-L1-positive tumours in the frontline setting, achieved an objective response to anti-PD-1 monotherapy.4, 11 The combination of nivolumab plus ipilimumab in previously untreated patients with metastatic melanoma yielded a response rate of 72% among patients who were PD-L1-positive and 55% among patients who were PD-L1-negative.4 However, the prospect of broad therapeutic efficacy of immune checkpoint blockers across multiple tumour histologies remains elusive, such as in the treatment of pancreatic ductal adenocarcinoma and metastatic castration-resistant prostate cancer, which are largely resistant to checkpoint targeting approaches.
Although early murine studies2 encouraged the notion that immune checkpoint blockers can engender long-lived protection against neoplasms, clinical follow-up results have disputed these expectations. For example, in the EORTC 18071 trial,6, 7 more than half of high-risk patients with stage III melanoma randomised to receive adjuvant ipilimumab had disease relapse, with a median recurrence-free survival of 26·1 months. In the KEYNOTE-001 trial,3 about one in four patients with metastatic melanoma who achieved an initial objective response to pembrolizumab subsequently had disease progression during follow-up (median 21 months). These results indicate that a substantial proportion of patients treated with immune checkpoint inhibitors might eventually acquire therapeutic resistance.
Enumerating the underlying mechanisms of de-novo (or primary) and acquired resistance to immune checkpoint targeting strategies has thus become a logical next step for cancer research. In this Review, we set out an organising framework (figure 1) for understanding immune-escape mechanisms in these contexts. In addition, we highlight emerging treatment approaches that might prolong the efficacy of immune checkpoint blockers or enable immunotherapy to impinge on previously intractable cancer types.
Section snippets
Two sides of the same coin?
Research during the past decade has identified a myriad of mechanisms that cause primary resistance to immune checkpoint blockade. By contrast, until recently, very little was understood about the acquired resistance pathways that underlie delayed relapses in patients who have received immunotherapy. Nevertheless, substantial parallels exist in the mechanisms of tumour escape for both primary and acquired resistance, suggesting a unifying conceptual framework that could provide greater
Defective tumour immunorecognition
Recognition of cancer cells by the adaptive immune system is the most important requirement for tumour rejection, and encompasses the individual steps of tumour antigen presentation and priming of naive T cells. This multistep process appears to be deregulated in many immunotherapy-resistant tumours (figure 2).
Insensitivity to immune effector molecules
Tumour destruction is classically conceived to be principally affected through perforin-mediated and granzyme-mediated lysis. However, T-cell effector cytokines, such as interferon-γ, directly help to restrain tumour growth by exerting direct antiproliferative and proapoptotic effects on cancer cells, and indirectly help via upregulation of tumour antigen presentation machinery (eg, inducible proteasome subunits, transporter associated with antigen processing 1/2, and MHC complex).
Interferon-γ
Tumour microenvironment and neovasculature
The immunoresistant niche is formed by cancer cells and other components of the tumour ecosystem (figure 4). Elucidation of an innate immune checkpoint blocker resistance-related transcriptional signature, which is associated with many cancer cell non-autonomous pathways, including angiogenesis, extracellular matrix remodelling, and wound healing,61 seems to support this point.
Tumour plasticity and stemness
Therapy-induced inflammation is known to promote tumour plasticity and phenotypic heterogeneity among cancer cells, which underpins therapeutic resistance to cytotoxic drugs, radiotherapy, and targeted therapies. A pertinent question that arises is whether reactive immune infiltrates might also be responsible, however paradoxically, for promoting resistance to immunotherapies. Indeed, augmented expression of genes (eg, AXL, TWIST2, WNT5A, LOXL2, ROR2, TAGLN, and FAP) involved in the
Enteric microbiome
The intestinal microbiota is increasingly recognised to interact with therapeutic outcomes for a host of disease conditions, including obesity, multiple sclerosis, arthritis, and psoriasis, albeit in complex and poorly understood ways. Several human and animal studies96, 97, 98, 99, 100 have shown that gut-residing commensal bacteria might likewise dictate the efficacy of immune checkpoint blockers in cancer immunotherapy.
The intriguing associations between microbiome diversity and non-response
Cooption of alternative immune checkpoints
During checkpoint blockade with anti-CTLA-4 and anti-PD-1/PD-L1 inhibitors, multiple inhibitory checkpoints might become coordinately upregulated because of interferon signalling55, 102 and activation of various pathways103 (eg, phosphoinositide 3-kinase-AKT) in tumour-infiltrating lymphocytes, eventually leading to therapeutic failure. For instance, TIM-3 upregulation has been detected in growing lesions from patients with lung adenocarcinoma who initially had a partial response to PD-1
Conclusion
The advent of checkpoint blockade immunotherapy has revolutionised treatment frameworks for many malignancies. However, the major limitation of single-agent immune checkpoint blockade is the ubiquity of primary resistance and the emergence of acquired resistance in a subset of patients who show a durable response. We therefore envisage that the next decade of research will focus on making conceptual progress to rationalise and broaden the utility of immune checkpoint targeting strategies.
In
Search strategy and selection criteria
References (111)
- et al.
Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial
Lancet Oncol
(2015) - et al.
Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial
Lancet Oncol
(2016) - et al.
Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial
Lancet
(2016) - et al.
Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial
Lancet Oncol
(2017) - et al.
Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial
Lancet Oncol
(2016) - et al.
Nivolumab versus standard, single-agent therapy of investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): health-related quality-of-life results from a randomised, phase 3 trial
Lancet Oncol
(2017) - et al.
Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial
Lancet Oncol
(2016) - et al.
Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial
Lancet Oncol
(2017) - et al.
Genomic correlates of immune-cell infiltrates in colorectal carcinoma
Cell Rep
(2016) - et al.
Molecular and genetic properties of tumors associated with local immune cytolytic activity
Cell
(2015)