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.
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.
Downloads (link to download the article as PDF)
Download citations (links to download the citations from this article in formats compatible with various reference manager tools)
Open citations (links to open the citations from this article in various online reference manager services)
Long noncoding RNAs (lncRNAs) are often associated with polysomes, indicating coding potential. However, only a handful of endogenous proteins encoded by putative lncRNAs have been identified and assigned a function. Here, we report the discovery of a putative gastrointestinal tract-specific lncRNA (LINC00675) that is regulated by the pioneer transcription factor FOXA1 and encodes a conserved small protein of 79 amino acids which we termed FORCP (FOXA1-Regulated Conserved Small Protein). FORCP transcript is undetectable in most cell types but is abundant in well-differentiated colorectal cancer (CRC) cells where it functions to inhibit proliferation, clonogenicity and tumorigenesis. The epitope-tagged and endogenous FORCP protein predominantly localizes to the endoplasmic reticulum (ER). In response to ER stress, FORCP depletion results in decreased apoptosis. Our findings on the initial characterization of FORCP demonstrate that FORCP is a novel, conserved small protein encoded by a mis-annotated lncRNA that regulates apoptosis and tumorigenicity in well-differentiated CRC cells.
New therapeutic targets for oral squamous cell carcinoma (OSCC) are urgently needed. We conducted genome-wide CRISPR-Cas9 screens in 21 OSCC cell lines, primarily derived from Asians, to identify genetic vulnerabilities that can be explored as therapeutic targets. We identify known and novel fitness genes and demonstrate that many previously identified OSCC-related cancer genes are non-essential and could have limited therapeutic value, while other fitness genes warrant further investigation for their potential as therapeutic targets. We validate a distinctive dependency on YAP1 and WWTR1 of the Hippo pathway, where the lost-of-fitness effect of one paralog can be compensated only in a subset of lines. We also discover that OSCCs with WWTR1 dependency signature are significantly associated with biomarkers of favorable response toward immunotherapy. In summary, we have delineated the genetic vulnerabilities of OSCC, enabling the prioritization of therapeutic targets for further exploration, including the targeting of YAP1 and WWTR1.