Cancer is a very interesting disease if you think about it from the SELF/non-SELF boundary. Cancer cells originate from own cells. So, it makes sense not to get eliminated. However, recent studies indicate they are different enough to be recognized by immune cells. In addition, because of the success of immune checkpoint inhibitors, many researchers and pharma companies investigate the possibility of developing new drugs in the same direction. But if cancer cells are different enough, why are they not eliminated during disease progression? Is this because of the failure of the immune system? Some think ‘Yes’. But I would say ‘No’ in most cases. In my view, cancer is the consequence of proper immune responses. That is why many patients have unnoticeable cancer progression until the late stages because of the lack of disturbing symptoms.
In my previous essay, “SELF vs non-SELF,” I used a show window of a small shop as an analogy to explain the MHC repertoire in each somatic cell. Here, I would like to use that analogy again. A tissue is a shopping street with multiple small stops (i.e. cells). The same cell types mean that displaying almost the same items on trays. At viral infection, many shops on the street are infected simultaneously. Their show windows quickly and drastically change to viral-derived products on the top shelf. In addition, they advertise their presence with flyers. Inflammation. No way to be missed. Then, how about cancer cells? How do things start? We can guess that the items on the show window do not change much. Mutations do not drastically change protein abundance in the cell. Perhaps the early mutations do nothing or make minimal changes on the bottom shelf where minor items are presented. Of course, no flyer. Hardly noticeable.
Whenever new changes are introduced, that only happens in a single shop and, in most cases, on the minor or no items - this does not mean functionally minor in the cell, but abundance. Keep changing the displays this way. The changes are easily overlooked and tolerated. The second shop reproduces the same display as the first (i.e., cell division). Can we capture the changes? No way! In addition, no chance of inflammation by mutations. For inflammation to happen, we need molecular reasons!! Because there is no reason for inflammation, peripheral tolerance is likely the consequence. Enough differences are detectable when normal and the endpoints of cancer cells are compared. However, as the gradual changes in minor peptides in a single cell each time without a surge of inflammation, T-cells can not eliminate emerging cancer cells. (If they can, we do not have Cancer.) Without inflammation, the properly processed MHC repertoire on cancer cells is recognized as a part of SELF. Thus, although cancer cells are different enough from normal cells, the process generating their differences prevents their elimination. Because the mechanism controlling the SELF/non-SELF boundary is properly working, i.e. the immune regulatory mechanism, we develop Cancer.
Is there any way to shift the boundary of SELF vs non-SELF to eliminate SELF-diverged cancer cells? It is possible. Since the SELF/non-SELF boundary is set by an abundance of peptides and affinity of TCRs, if we can change either condition, the boundary should be shifted. What can we do? The first possibility is inducing drastic changes in the show window display. Induction of high cellular stress can drastically change their MHC repertoire. Chemotherapy is primarily targeting cancer cells and providing high genotoxic stress. This can induce apoptosis and simultaneously the change in the MHC repertoire. This increases the chance of being recognized and eliminated by T-cells. However, since those genotoxic drugs also affect the activated T-cells, their effectiveness is unfortunately limited.
The second possibility is vaccination. Vaccination is changing T-cells' functional avidity (sensitivity of T-cell activation) and increasing the T-cell population carrying specific TCRs recognizing the target antigens to detect low-abundance peptides. In this vaccination process, antigen-presenting cells (APCs like tissue residential macrophages and dendritic cells) and MHCII play an essential role. Co-injection of adjuvant activates innate immune cells with PPRMs, meaning a surge of inflammation. APCs simultaneously engulf the inoculated immunogen and digest it. In APCs, the engulfed digested peptides, usually foreign peptides, are presented on MHCIIs with a distinct preference for peptide selection from MHCIs. A surge of inflammation and antigen presentation on MHCII in APCs can activate specific T-cells that carry the TCR recognizing it. The specific T-cell population expands, enhancing their functional avidity (sensitivity). The enhanced functional avidity is memorized.
Since cancer cells originate from own cells, there is no foreign protein. However, recent studies revealed tumour-specific antigens (TSAs) in cancer cells. What could be TSAs? People often think the peptides carrying the point mutations and junctions of deletion and gene fusion would be TSAs. Although this is true, those are usually not abundant proteins. Their presence in the MHC repertoire could be low or none.
On the other hand, dysregulation of epigenetic silencing, often observed in cancer cells, can impact the MHC repertoire. For example, retrotransposons in the genome are silenced in normal somatic cells but re-expressed in cancer cells. High stress due to high replication, transcription and translation can cause cryptic transcription and translation from non-coding genomic regions and introns, respectively. Non-coding frames can also be translated for short peptides. These stress-related peptides can be TSAs, and some are abundant. Unfortunately, the previous peptidome analysis on MHCs could not capture them because their data was bioinformatically curated based on the coding sequence database.
Although TSAs exist as distinct peptides in cancer cells, the cells carrying them are not eliminated due to their slow generation process described above. The properly processed TSAs on MHCI without inflammation are likely already gaining peripheral tolerance. To overcome this peripheral tolerance, antigen presentation through MHCII is essential. To display peptides on MHCII, the original antigens need to be engulfed by APCs. When a cell goes apoptosis, the cell gets engulfed by APCs. However, in this way, there is no or minor inflammation and the proteins in the dying cell are properly processed before engulfment. This cannot overwrite the peripheral tolerance. Inducing apoptosis is not a good strategy to activate immunoreactivity against cancer cells.
On the other hand, necrosis appears promising. When necrosis happens, various cytoplasmic proteins leak out without proper processing. Some act as damage associate molecular patterns (DAMPs) to activate inflammation. Simultaneously, the leaked proteins are engulfed by APCs and processed within APCs for presentation on MHCII. A new repertoire of epitopes, including TSAs, is presented with inflammation on the second tray, MHCII. I do not know if the peripheral tolerance of abundant antigens is cleared (regulatory T-cells back to killer T-cells) or if T-cells carrying TCRs with weak affinities against low-intermediate abundant antigens can get activated and develop into T-cells with high functional avidity (a new T-cell population is recruited). This shift would permit the detection of low-abundant TSAs on MHCIs.
Necrosis is known to happen in tumours. Then, why are those tumours not eliminated after necrosis-induced T-cell activation? First, DAMPs appear not to be the best inflammatory initiators. Generally, sterile injuries heal faster than open injuries exposed to environmental pathogens. For vaccination, adjuvants are co-injected with antigens. Adjuvants comprise Pathogen-associated Molecular Patterns (PAMPs) molecules, which can activate Pathogen Recognition receptors in APCs to induce inflammation. Second, the situation in which necrosis is induced during cancer progression is not optimal for T-cell activation. The necrosis in tumours is primarily caused by hypoxia and nutrient deprivation. This environment is not suitable for activation of APCs and T-cells. Even when specific T-cells are activated, they are exhausted. However, those exhausted T-cells are likely the ones responding to checkpoint inhibitors.
Building the SELF/non-SELF boundary is essential for the integrity and continuum of species. Defining non-SELF is relatively easy and permits a sharp clear boundary. When metazoans emerged, the SELF/non-SELF recognition mechanisms changed from the DNA sequence to the organismal property. Although metazoans do not use sequence-based recognitions like restriction enzymes and CRISPRs, all metazoans have innate immunity that recognizes common properties of pathogens and cellular damage. When vertebrates evolve, adaptive immunity is established. The acquisition of adaptive immunity allows the vertebrates to have relative longevity and larger body sizes. As a trade-off, we gain unique diseases like cancer.