Answer by Tirumalai Kamala:
The word Tolerance inhabits a grey area within the immunology lexicon. Immunologists frequently use the word tolerance to denote absence of immune response when often a careful examination of their experimental methodology reveals that their actual intention was to denote absence of anticipated immune response, typically a response they routinely examine using their lab’s immunology toolkit. Some readouts are observational such as CD4 T cell responses, others are functional such as lysis by neutralizing antibody or cytotoxic CD8 T cells or change in size or number of experimentally induced tumor. Further, many immunologists also use tolerance to denote certain classes of immune responses such as those associated with tissue or organ transplant acceptance or those associated with mucosal sites or those associated with tumor growth. Again, these are not absence of immune response. Rather, they are presence of certain types of immune response.
Important as these distinctions are, let’s expand the conceptual landscape beyond these technicalities and make even more explicit the attributes of tumors and immune function at play. Does a tumor grow in spite of an effective immune response against it or because it successfully subverts such immune responses? Parsed in this manner, there appear two possibilities for tumor survival and growth. Either immune function tries to get rid of the tumor but fails, or the tumor co-opts immune function to survive and grow. Data support both possibilities, suggesting we could tweak immune function and harness it to rid the body of tumors.
I’ll explore two themes in this answer. One, since we typically assume immunity deals with infections, what is the association between infections and tumors? Do infections promote or inhibit tumors? Two, once a tumor establishes, what approaches does it take to co-opt or keep immunity at bay?
Do Infections Promote or Inhibit Tumors?
What is different about the immunological history of people who don’t develop tumors? Is it possible such individuals make effective anti-tumor immune responses and get rid of them? If so, could epidemiological studies reveal what is different about them? A trove of such studies suggest that a history of acute infections could endow us with better capacity to prevent or eradicate tumors, in contrast to chronic infections or inflammatory syndromes (1, 2, 3, 4, 5, 6). What types of infections confer anti-tumor protection? Infections increasingly rare in industrialized countries, such as pulmonary TB, pneumonia, Staphylococcus aureus, and other infections associated with fever over 38oC. These sound suspiciously similar to the factors that empirically associated with spontaneous tumor remissions (7, 8). Here are some of these epidemiological studies linking a history of acute infections with resistance to tumors.
1. Babies who acquire acute infections at day-care centers appear to have lower risk for Acute Lymphoblastic Leukemia (ALL) (9).
2. Inverse relationship between childhood history of measles, chickenpox, rubella, mumps, pertussis with risk for Chronic Lymphoblastic Leukemia (CLL) (10).
3. Dairy farmers are apparently less likely to develop lung, bladder, pancreatic or esophageal cancers (11, 12), with higher exposure to cattle conferring greater protection, and protection waning when the farmers switch to other occupations. Some agriculture and cotton textile workers seem less likely to develop lung cancers (13). Here the protective exposure is different in kind to those in points 1 and 2 since it needs to be continual to confer anti-tumor protection. These studies suggest that certain occupational microbe(s)/microbial product(s) exposure could continually modulate immune function to confer anti-tumor protection but that they don’t induce a strong and stable immunological memory of the type that rids tumors.
4. Some vaccines may mimic the acute infection effect on immune function, and either train it appropriately and/or generate anti-tumor cross-reactivity. BCG, when given early in life and found to be protective against TB, also seems to protect from leukemia (14). So do the small pox Vaccinia and Yellow Fever vaccines (15, 16, 17, 18). I don’t think it is coincidence that all three are live organism vaccines. Robust and stable immunological memory appears to depend on constant exposure to live organisms.
While there are caveats and disputes regarding data interpretations associated with many of these epidemiological linkage studies, they embody the resurgence of interest in Coley‘s ideas, and perfectly complement the current renaissance in tumor immunology. How far we have come in 3 short decades! Over the course of the 20th century, with radiotherapy and chemotherapy touted as anti-tumor breakthroughs, clinical investigations of biological remedies requiring stricter regulatory compliance, and poor patenting prospects of, his revolutionary insight of harnessing immunity to rid the body of tumors faded to the extent that, as recently as the 1980s, studying tumor immunity was considered, “a seedy intellectual neighborhood of fantasy and wishful thinking, a landscape littered with the hulks of abandoned hypotheses and charred reputations” (8). We are also left with the key question. Are these associations causal or casual? In contrast to Coley‘s time, today, rather than directly plunging into human experimentation, we need to await animal model data for definitive proof of causality linkage between acute infections and resistance to tumors.
What does a Tumor do to co-opt or keep Immunity at bay?
What about tumors themselves? Do they reveal presence of immune responses? Solid tumors harbor many immune cells. These include lymphocytes (TIL; ) and (MDSC). These days, there are too many mouse model or in vitro human studies exploring these and other cells in ways that seem to me either too archaic, too boring or too esoteric. Once in a while, a study pops up exploring such an interesting idea that I remember it years later. Such a study was a mouse model of prostate cancer published in 2005 (19), which was among the first to show that cancer cells can impose such strong selection pressure on the surrounding tissue cells in their micro-environment that the latter end up hopelessly compromised in their function, helplessly in thrall to the tumor, a to the tumor’s . In this study, the tumor appeared to promote accumulation of specific that had undergone changes in their gene and proliferated locally to create a micro-environment that promoted the tumor’s growth. p53 is a tumor-suppressor gene that acts as a break on cell proliferation. Its loss indicates a runaway cell, one now endowed with the capacity for unchecked proliferation. Data from such studies beg the question what is a tumor? Can a tumor be so neatly, surgically, strictly delineated as we continue to believe? Does the distinction between tumor and normal tissue become more nebulous as the former grows and spreads? If a tumor co-opts normal cells to this extent, is it even conceivable that such co-opted cells go back to normalcy once the tumor is removed, whether surgically or by therapy or both?
If the tumor is a plant, and the tumor micro-environment the soil (20, 21, 22), isn’t this scenario akin to, where, in the wake of the havoc wreaked by the tumor plant, the tissue soil is depleted, denuded and no longer normal itself? If such is indeed the case, is it any wonder that strong anti-tumor immunity alone isn’t enough? With the tumor and co-opted tissue micro-environment cooperating to impose such strong selection pressure on anti-tumor immune cells, the latter also end up compromised, becoming TILs that cannot lyse tumor cells or MDSCs that inhibit TILs from trying to lyse tumor cells. Presence of immune cells in tumors is evidence of strong anti-tumor immunity alright, only it is not effective anti-tumor immunity. Since many changes are stable, such epigenetically changed tumor micro-environments may not only retain tumor-supporting propensity but also retain capability to subvert anti-tumor immunity . This suggests that such epigenetically modified tissue sites could continue to remain at increased risk of tumor recurrence even after a primary tumor is successfully removed.
Examined in this fashion, it seems clear that targeting tumor cells, tumor antigens and their blood supply alone won’t be enough to eliminate tumors. We must harness the surrounding tissue as well. And while we are at it, as part of the tumor eradication process, shouldn’t we consider approaches to re-train/re-educate the TILs, the MDSCs and other tumor-associated leukocytes? If the tumor induces in these immune cells stable epigenetic tumor-supporting changes, which it likely does, aren’t these cells likely to sustain tumors in the future as well, as and when such tumors arise, particularly in the same tissues as the original tumor? In other words, we also need to specifically target and neutralize the tumor’s efforts to co-opt the surrounding tissue micro-environment (23, 24) and anti-tumor immunity. We now better appreciate this imperative (25). To quote the authors of a recent review (26), “inhibition of chronic inflammation in the tumor micro-environment should be applied in conjunction with melanoma immunotherapies to increase their efficacy“. Such an approach will necessitate increasingly personalized approaches since tumor micro-environments tend to be heterogeneous, and vary from one person to another and from one tissue to another (27, 28).
4. Krone, B., et al. “Impact of vaccinations and infectious diseases on the risk of melanoma—evaluation of an EORTC case–control study.” European Journal of Cancer 39.16 (2003): 2372-2378.
14. Grange, J. M., and J. L. Stanford. “BCG vaccination and cancer.” Tubercle 71.1 (19titivity. 90): 61-64.
18. Mastrangelo, G., et al. “Does yellow fever 17D vaccine protect against melanoma?.” Vaccine 27.4 (2009): 588-591.
20. Paget, Stephen. “The distribution of secondary growths in cancer of the breast.” The Lancet 133.3421 (1889): 571-573.
21. Fidler, Isaiah J. “The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited.” Nature Reviews Cancer 3.6 (2003): 453-458.