Cancer Immunotherapy: A peptide puzzle

Why does cancer develop in situations where the immune system is perfectly capable of eliminating it?
  1. Jian Guan
  2. Nilabh Shastri  Is a corresponding author
  1. Johns Hopkins School of Medicine, United States

The primary function of the immune system is to detect and eliminate any abnormal cells in the body. To detect these abnormal cells, immune cells called 'killer cells' look for changes in the peptides that are present on the surface of all cells. In healthy cells these peptides stand for normal proteins made inside the cell. However, if new peptides are found, the killer cells take that as evidence of abnormality, such as a virus infection or cancer, and they destroy the abnormal cells to limit the spread of an infection or the growth of a cancer. So why do the killer cells fail to prevent the growth of some tumors in the first place?

The idea that immune system could contain the growth of tumors has been controversial for many decades (Burnet, 1967; Hellström et al., 1968). However, the recent success of immunotherapy – which was highlighted when the 2018 Nobel Prize in Physiology or Medicine was awarded to James Allison and Tasuku Honjo – has dramatically improved the prospects of cancer treatment. Many, but not all, patients with previously incurable cancers have effectively been cured by immunotherapy.

Making further improvements, to help patients who are not responsive to immunotherapy at present, will require a better understanding of how the body regulates the response of killer cells to cancer. This is especially important during the early stages of cancer when there are relatively few abnormal cells. Now, in eLife, David Scheinberg and colleagues at Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center – including Ron Gejman and Aaron Chang as joint first authors – report the results of studies in which an elegant new experimental platform called PresentER was used to study the response of killer cells to thousands of different peptides in mice (Gejman et al., 2018).

Cancer cells were injected into immunocompetent mice and left to grow for several weeks. Some cancer cells were detected and destroyed by the immune system, while others failed to be eliminated and grew into tumors. When Gejman et al. analyzed the cells in these tumors they found to their surprise that, in general, the presence of a particular peptide did not result in detection and rejection: this was also true even for immunogenic peptides (that is, for peptides that are known to elicit a strong response from the immune system). Rather, the tumors that developed tended to contain cells expressing a wide range of different immunogenic peptides. This suggests that the immune system can only detect and reject a tumor when a certain fraction of the cells in the tumor display the same immunogenic peptide. This behavior is particularly interesting because it is similar to what is seen in human cancer patients who do not benefit from immunotherapy (McGranahan et al., 2016).

Why does the immune system fail to reject cancer cells that display a heterogenous mix of peptides? To explore this question Gejman et al. injected mice with mixtures of cancer cells in which some of the cells displayed immunogenic peptide, while the rest displayed non-immunogenic peptides. When the fraction of cells with immunogenic peptides was low, the cells were not eliminated (Figure 1). Moreover, the minimum fraction required to generate an effective immune response varied between different peptides, suggesting that some as-yet-unknown features of the peptides were important.

Schematic illustration of the anti-cancer immune response.

(a) Gejman et al. found that a cancer that contains a large fraction of immunogenic tumor cells of the same type (shown in green) can be effectively rejected by the immune system of the mouse (left), whereas a cancer that contains a small fraction of immunogenic tumor cells will not be rejected (right). (b) However, a cancer that contains a large fraction of immunogenic tumor cells of different types (shown in different colors) will not be rejected. This behavior observed by Gejman et al. in mice is similar to that seen in humans who do not respond to immunotherapy (McGranahan et al., 2016).

The work of Gejman et al. establishes that peptide heterogeneity within cancer cells has an impact on the detection of cancer and also on the responsiveness to immunotherapy. It also highlights the influence of the fraction of the immunogenic cells in a given cancer, a factor that has largely been underestimated up until now, and the need for a better understanding of the role of immunogenic peptides in the generating an effective immune response to cancer. And last, but not least, this latest work shows the potential of the PresentER approach to be used in large-scale screening studies of potentially immunogenic peptides.


Article and author information

Author details

  1. Jian Guan

    Jian Guan is in the Department of Pathology, Johns Hopkins School of Medicine, Baltimore, United States

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0118-6578
  2. Nilabh Shastri

    Nilabh Shastri is in the Department of Pathology, Johns Hopkins School of Medicine, Baltimore, United States

    For correspondence
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8060-3025

Publication history

  1. Version of Record published: December 7, 2018 (version 1)


© 2018, Guan and Shastri

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.


  • 2,264
    Page views
  • 242
  • 1

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Jian Guan
  2. Nilabh Shastri
Cancer Immunotherapy: A peptide puzzle
eLife 7:e41524.
  1. Further reading

Further reading

    1. Biochemistry and Chemical Biology
    2. Cancer Biology
    Pengfei Guo, Rebecca C Lim ... Hui Zhang
    Research Article Updated

    The Polycomb Repressive Complex 2 (PRC2) methylates H3K27 to regulate development and cell fate by transcriptional silencing. Alteration of PRC2 is associated with various cancers. Here, we show that mouse Kdm1a deletion causes a dramatic reduction of PRC2 proteins, whereas mouse null mutation of L3mbtl3 or Dcaf5 results in PRC2 accumulation and increased H3K27 trimethylation. The catalytic subunit of PRC2, EZH2, is methylated at lysine 20 (K20), promoting EZH2 proteolysis by L3MBTL3 and the CLR4DCAF5 ubiquitin ligase. KDM1A (LSD1) demethylates the methylated K20 to stabilize EZH2. K20 methylation is inhibited by AKT-mediated phosphorylation of serine 21 in EZH2. Mouse Ezh2K20R/K20R mutants develop hepatosplenomegaly associated with high GFI1B expression, and Ezh2K20R/K20R mutant bone marrows expand hematopoietic stem cells and downstream hematopoietic populations. Our studies reveal that EZH2 is regulated by methylation-dependent proteolysis, which is negatively controlled by AKT-mediated S21 phosphorylation to establish a methylation-phosphorylation switch to regulate the PRC2 activity and hematopoiesis.

    1. Cancer Biology
    Sen Qin, Yawei Xu ... Zheng Zhang
    Research Article

    Pheochromocytomas (PCCs) are rare neuroendocrine tumors that originate from chromaffin cells in the adrenal gland. However, the cellular molecular characteristics and immune microenvironment of PCCs are incompletely understood. Here, we performed single-cell RNA sequencing (scRNA-seq) on 16 tissues from 4 sporadic unclassified PCC patients and 1 hereditary PCC patient with Von Hippel-Lindau (VHL) syndrome. We found that intra-tumoral heterogeneity was less extensive than the inter-individual heterogeneity of PCCs. Further, the unclassified PCC patients were divided into two types, metabolism-type (marked by NDUFA4L2 and COX4I2) and kinase-type (marked by RET and PNMT), validated by immunohistochemical staining. Trajectory analysis of tumor evolution revealed that metabolism-type PCC cells display phenotype of consistently active metabolism and increased metastasis potential, while kinase-type PCC cells showed decreased epinephrine synthesis and neuron-like phenotypes. Cell-cell communication analysis showed activation of the annexin pathway and a strong inflammation reaction in metabolism-type PCCs and activation of FGF signaling in the kinase-type PCC. Although multispectral immunofluorescence staining showed a lack of CD8+ T cell infiltration in both metabolism-type and kinase-type PCCs, only the kinase-type PCC exhibited downregulation of HLA-I molecules that possibly regulated by RET, suggesting the potential of combined therapy with kinase inhibitors and immunotherapy for kinase-type PCCs; in contrast, the application of immunotherapy to metabolism-type PCCs (with antigen presentation ability) is likely unsuitable. Our study presents a single-cell transcriptomics-based molecular classification and microenvironment characterization of PCCs, providing clues for potential therapeutic strategies to treat PCCs.