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07 Dec 2017

An article by John Haanen released in occasion of ESMO Immuno-Oncology Congress 2017, 7-10 December, Geneva, Switzerland.

Cancer Immunotherapy: Escape of Response

Immunotherapy with monoclonal antibodies that block T-cell inhibitory pathways—immune checkpoint blockade—has profoundly changed the treatment paradigm for many advanced cancers, including melanoma, non-small cell lung cancer (NSCLC), Hodgkin lymphoma and others (1). The effect of antibodies that block cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), and antibodies that block programmed death 1 (PD-1) or its main ligand PD-L1, is to unleash the activity of an endogenous tumour-specific T-cell pool (2). However, the majority of patients do not respond to checkpoint blockade (primary resistance) and, of those who experience tumour regression, a proportion will relapse (secondary or acquired resistance) (Table 1) (3).

The identification and characterisation of mechanisms underlying escape of response is progressing (see summary in Figure 1) and remains a research priority. This short review summarises some of the known mechanisms of primary and acquired resistance to immune checkpoint inhibitors (ICPis), particularly mutations affecting interferon (IFN) signalling and of antigen-presenting machinery.

The IFN-γ pathway is a key player in immune checkpoint inhibitor resistance

Tumour infiltrating T-cells destroy cancer cells during PD-1 blockade and form part of the known indicators of tumour responsiveness to anti-PD-1 in melanoma—namely the presence of CD8+ tumour infiltrating lymphocytes (TIL) and high density TIL at the invasive tumour margin (4) and the presence of an IFN-γ gene signature (5). These features of an anti-PD-1 responsive tumour could be subverted and selected for in the development of resistance. This has been borne out in recent studies, with the expression or repression of specific genes and pathways that prevent immune cell infiltration and/or immune cell function within the tumour microenvironment identified as mechanisms of primary and secondary resistance (Figure 1).   

On recognising tumour antigen, tumour-specific T-cells produce IFN-γ. This leads to the expression of many genes via the IFN receptor within the tumour microenvironment (including tumour cells), the Janus kinases JAK1 and JAK2, and the signal transducers and activators of transcription (STAT) (3). This pathway exerts a largely anti-tumour effect through enhanced antigen presentation via increased expression of proteins including MHC, increased immune cell recruitment and through tumour cell proliferation arrest and apoptosis. But in addition, IFN-γ signals cancer cells to adaptively express PD-L1, thus inactivating tumour-specific T-cells and a form of tumour adaptive resistance.

A recent, ground-breaking study has demonstrated that the genetic mechanisms of acquired resistance to PD-1 therapy also involve mutations in the genes affecting the IFN pathway and the antigen-presentation pathway (6). In this study, longitudinal tumour biopsies from paired baseline and relapsing lesions in melanoma patients with an initial objective response were investigated via whole-exome sequencing of tumour tissue and immune profiling to identify mechanisms underlying therapeutic resistance to the anti-PD-1 therapy, pembrolizumab. Whole-exome sequencing revealed resistance-associated loss of function mutations in the genes encoding JAK1 or JAK2 in two cases of tumour relapse and a truncating mutation in the gene encoding the antigen-presenting protein β2-microglobulin (B2M). T-cell recognition of tumour antigen was maintained despite the JAK mutations. In vitro, the JAK mutations conferred tumour cell resistance to IFN-γ (JAK2 mutation) or IFN-α/β/γ (JAK1 mutation) and with reduced STAT1, STAT3, and IRF1 phosphorylation and failure to upregulate TAP1 and HLA class I and PD-L1 expression was lost (JAK2 mutation). Previous studies had identified cases of acquired resistance to IL-2 and TIL adoptive cell transfer through loss of B2M and associated lack of HLA class I. A B2M truncating mutation was identified in one patient with acquired resistance to pembrolizumab, which led to loss of surface expression of MHC class I. Of further interest, tumour immune response after relapse through visualisation of CD8+ T-cell infiltrate and PD-L1 expression showed that the T-cell activity was almost exclusively at the margin of invasion (6). This suggested that the acquired resistance to anti-PD-1 based therapy is associated with a reversion of the tumour to a lymphocyte-excluded state (7).

JAK1 and JAK2 disruption in the form of homozygous loss-of-function mutations have now been identified in cases of primary resistance to PD-1 blockade in patients with metastatic melanoma and DNA mismatch repair deficient colon cancer patients, but these initial findings are in few patients (1/23 melanoma and 1/16 colon cancer) (8). In human melanoma cell lines, 2/48 harboured JAK1/2 mutations, with the functional consequences of loss of reactive PD-L1 expression and response to IFN-γ resulting in primary resistance to antibody blockade of PD-1 (8).

A CRISPR-based genome-wide screen has recently revealed that expression of more than 100 key genes is required for the immune system and consequently ICPis to effectively target tumour cells (7). Somatic gene mutations can alter the vulnerability of cancer cells to T-cell-based immunotherapies and this study demonstrates that mutations in genes involved in antigen presentation and T-cell activation are associated with acquired resistance (9). Among the genes validated using different cancer cell lines and antigens, this study identified multiple loss-of-function mutations in the apelin receptor (APLNR) of immunotherapy resistant tumours. The study indicated that APLNR interacts with JAK1 to modulate IFN-γ responses in tumours and that its functional loss reduces the efficacy of ICPis.

Other mechanisms of tumour T-cell exclusion

A melanoma-cell-intrinsic oncogenic pathway has been identified, which offers a mechanism by which tumour-intrinsic β-catenin signalling leads to T-cell exclusion (10). The β-catenin expression suppresses CCL4 synthesis, and results in the exclusion of a critical subset of antigen-presenting cells from the tumour—CD103+ dendritic cells with the consequence of T-cell exclusion. This resistance mechanism has been unravelled in preclinical settings, and subsequently has been investigated in human cancers as well. It appears that about 10% of human cancers have an activated β-catenin pathway that could account for primary resistance to immunotherapy (11).

Another observation in human melanomas was the heterogeneous expression of the tumour suppressor PTEN. Loss of PTEN leads to an activated PI3K pathway. Interestingly, in tumour areas with PTEN loss, CD8+ T-cell infiltrates were completely lacking (12). The objective response rate in metastatic melanoma patients treated with anti-PD-1 were predominantly found in PTEN proficient tumours, corroborating this finding as a possible immune escape mechanism.

Overcoming resistance to immunotherapy

Extensive research efforts are currently underway to develop strategies to overcome resistance to ICPis. These strategies predominately focus on the development of combination therapies using therapeutic agents targeting different pathways to overcome resistance. This includes the combined use of checkpoint inhibitors, and other strategies including viral therapy, which has been shown capable of changing the tumour microenvironment from an immunologically “cold”, or T-cell excluded, to a “hot” tumour and with restored response to pembrolizumab in malignant melanoma (2,13). A better understanding of the molecular mechanisms underlying therapeutic resistance will facilitate the rational design of alternative therapies to overcome resistance.  

  1. Topalian SL. Targeting immune checkpoints in cancer therapy. JAMA 2017; 318(17):1647-1648.
  2. Haanen JBAG. Converting cold into hot tumors by combining immunotherapies. Cell 2017; 170(6):1055-1056.
  3. Sharma P, Hu-Lieskovan S, Wargo JA, et al. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 2017; 168(4):707-723.
  4. Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014; 515(7528):568-571.
  5. Ayers M, Lunceford L, Nebozhyn M, et al. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest 2017; 127(8):2930-2940.
  6. Zaretsky JM, Garcia-Diaz A, Shin DS, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med 2016; 375(9):819-829.
  7. Andrews MC, Wargo JA. Immunotherapy resistance: the answers lie ahead - not in front - of us. J Immunother Cancer 2017; 5:10.
  8. Shin DS, Zaretsky JM, Escuin-Ordinas H, et al. Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations. Cancer Discov 2017; 7(2):188-201.
  9. Patel SJ, Sanjana NE, Kishton RJ, et al. Identification of essential genes for cancer immunotherapy. Nature 2017; 548(7669):537-542.
  10. Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 2015; 523(7559):231-235
  11. Luke JJ, Bao R, Spranger S, et al. Correlation of WNT/β-catenin pathway activation with immune exclusion across most human cancers. J Clin Oncol 34, no. 15_suppl (May 2016) 3004-3004.
  12. Peng W, Chen JQ, Liu C, et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov 2016; 6:202–216.
  13. Ribas A, Dummer R, Puzanov I, et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell 2017; 170(6):1109-1119
Table 1. Resistance to immune checkpoint inhibitors




  • Lack of response to initial immunotherapy
  • Tumour not recognised by immune system
  • May include adaptive immune resistance 


  • Tumour recognised by the immune system but protects itself by adaptation
  • Due to evolving nature of the immune system/cancer cell interaction, this can manifest as primary resistance, mixed response or acquired resistance


  • Tumour initially responds to immunotherapy, but loss of response occurs after a period of time and tumour relapses/progresses
Figure 1. Intrinsic mechanisms of primary, adaptive and acquired resistance to immune checkpoint inhibitors
Cancer Immunotherapy: Escape of Response

Reprinted from Cell 168(4) Sharma P, et al. Primary, adaptive, and acquired resistance to cancer immunotherapy (2017) with permission from Elsevier.

ACT, adoptive cell transfer; B2M, β2-microglobulin; HLA, Human Leukocyte Antigen; IFN, interferon; LAG-3, lymphocyte-activation gene 3; TAM, TYRO3, AXL and MERTK family; MAPK, mitogen-activated protein kinase; MHC, major histocompatibility complex; PD-1, programmed cell death-1; PI3K, phosphatidylinositide 3-kinases; TAP, transporter associated with antigen presentation; TCR, T-cell receptor; TIM-3, T-cell immunoglobulin and mucin-domain containing protein 3; VISTA, V-domain immunoglobulin-containing suppressor of T-cell activation.

Last update: 07 Dec 2017

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