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Cancer Immunotherapy: A peptide puzzle
Jian Guan,
Nilabh Shastri ,
Johns Hopkins School of Medicine, United States;
Insight Dec 7, 2018
Main text
Why does cancer develop in situations where the immune system is perfectly capable of eliminating it?
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.
Immunological aspects of malignant disease
FM Burnet
The Lancet 1:1171–1174.
Rejection of immunogenic tumor clones is limited by clonal fraction
RS Gejman
AY Chang
HF Jones
K DiKun
AA Hakimi
A Schietinger
DA Scheinberg
Cellular and humoral immunity to different types of human neoplasms
I Hellström
KE Hellström
GE Pierce
JP Yang
https://doi.org/10.1038/2201352a0
Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade
AJ Furness
R Rosenthal
S Ramskov
R Lyngaa
SK Saini
M Jamal-Hanjani
GA Wilson
NJ Birkbak
CT Hiley
TB Watkins
S Shafi
N Murugaesu
R Mitter
AU Akarca
J Linares
T Marafioti
JY Henry
EM Van Allen
D Miao
B Schilling
D Schadendorf
LA Garraway
V Makarov
NA Rizvi
A Snyder
MD Hellmann
T Merghoub
JD Wolchok
SA Shukla
CJ Wu
KS Peggs
TA Chan
SR Hadrup
C Swanton
https://doi.org/10.1126/science.aaf1490
Jian Guan
Jian Guan is in the Department of Pathology, Johns Hopkins School of Medicine, Baltimore, United States
Nilabh Shastri
Nilabh Shastri is in the Department of Pathology, Johns Hopkins School of Medicine, Baltimore, United States
nshastr3@jhmi.edu
Version of Record published: December 7, 2018 (version 1)
© 2018, Guan and Shastri
tumor antigens
genetic heterogeneity
tumor evolution
tumor resistance to immune response
Ron S Gejman et al.
Research Article Nov 30, 2018
Tumors often co-exist with T cells that recognize somatically mutated peptides presented by cancer cells on major histocompatibility complex I (MHC-I). However, it is unknown why the immune system fails to eliminate immune-recognizable neoplasms before they manifest as frank disease. To understand the determinants of MHC-I peptide immunogenicity in nascent tumors, we tested the ability of thousands of MHC-I ligands to cause tumor subclone rejection in immunocompetent mice by use of a new 'PresentER' antigen presentation platform. Surprisingly, we show that immunogenic tumor antigens do not lead to immune-mediated cell rejection when the fraction of cells bearing each antigen ('clonal fraction') is low. Moreover, the clonal fraction necessary to lead to rejection of immunogenic tumor subclones depends on the antigen. These data indicate that tumor neoantigen heterogeneity has an underappreciated impact on immune elimination of cancer cells and has implications for the design of immunotherapeutics such as cancer vaccines.
Re-expression of SMARCA4/BRG1 in small cell carcinoma of ovary, hypercalcemic type (SCCOHT) promotes an epithelial-like gene signature through an AP-1-dependent mechanism
Krystal Ann Orlando et al.
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and aggressive form of ovarian cancer. SCCOHT tumors have inactivating mutations in SMARCA4 (BRG1), one of the two mutually exclusive ATPases of the SWI/SNF chromatin remodeling complex. To address the role that BRG1 loss plays in SCCOHT tumorigenesis, we performed integrative multi-omic analyses in SCCOHT cell lines +/- BRG1 reexpression. BRG1 reexpression induced a gene and protein signature similar to an epithelial cell and gained chromatin accessibility sites correlated with other epithelial originating TCGA tumors. Gained chromatin accessibility and BRG1 recruited sites were strongly enriched for transcription-factor-binding motifs of AP-1 family members. Furthermore, AP-1 motifs were enriched at the promoters of highly upregulated epithelial genes. Using a dominant-negative AP-1 cell line, we found that both AP-1 DNA-binding activity and BRG1 reexpression are necessary for the gene and protein expression of epithelial genes. Our study demonstrates that BRG1 reexpression drives an epithelial-like gene and protein signature in SCCOHT cells that depends upon by AP-1 activity.
Loss of FLCN-FNIP1/2 induces a non-canonical interferon response in human renal tubular epithelial cells
Iris E Glykofridis et al.
Germline inactivating mutations in Folliculin (FLCN) cause Birt–Hogg–Dubé (BHD) syndrome, a rare autosomal dominant disorder predisposing to kidney tumors. FLCN is a conserved, essential gene linked to diverse cellular processes but the mechanisms by which FLCN prevents kidney cancer remain unknown. Here we show that deleting FLCN activates TFE3, upregulating its downstream E-box genes in human renal tubular epithelial cells (RPTEC/TERT1), including RRAGD and GPNMB, without modifying mTORC1 activity. Surprisingly, deletion of FLCN or its binding partners FNIP1/FNIP2 also induces interferon response genes, but independently of interferon. Mechanistically, FLCN loss promotes STAT2 recruitment to chromatin and slows cellular proliferation. Our integrated analysis identifies STAT1/2 signaling as a novel target of FLCN in renal cells and BHD tumors. STAT1/2 activation appears to counterbalance TFE3-directed hyper-proliferation and may influence the immune response. These findings shed light on unique roles of FLCN in human renal tumorigenesis and pinpoint candidate prognostic biomarkers.