Heliovaccination: Solar mediated immunity against cancer

Abstract

The protective effect of ultraviolet (UV) light against a host of malignancies is well characterised. It was recognised by WHO in their 2006 publication on the global burden of UV-mediated disease. The mechanism by which this oncoprotective effect occurs remains unclear. Vitamin D has been mooted as a potential mediator. However, the evidence does not support this. I suggest that UV irradiation of the skin produces nascent malignant and premalignant cells with associated generic tumor-specific antigens. These are eliminated by immunosurveillance resulting in adaptive immunity. The clonal expansion of these immune cells protects against tumors in other viscera, effectively immunising the host. The evidence for this “heliovaccination” is very strong. Childhood UV exposure protects against cancer in adulthood. Tumor naïve individuals possess anti-tumor antibodies. Antigen-presenting cells mobilise to the skin following specifically UVB skin irradiation. It is time to rethink the link between UV light and cancer.

1 BACKGROUND

The oncoprotective effect of ultraviolet (UV) light has been reported for over a century. In 1915, Hoffman observed that living at increasing latitudes from the equator was associated with an increasing risk of death due to cancer.¹ Twenty-five years later, Apperly noted that there was an inverse relationship between deaths due to cancer and solar irradiation. He observed that farmers working in the South had the highest skin cancer mortality rates but the lowest overall deaths from cancer.² He surmised that this “relative immunity to cancer is a direct effect of sunlight.” Vitamin D has been strongly suggested as the bio-transducer via which the oncoprotective effects of UV radiation are mediated.³ However vitamin D supplementation has not been observed to reduce cancer risks in randomised controlled trials and meta-analyses.^4-6

The evidence for the protective effect of sunlight against cancer is now almost incontrovertible. The World Health Organization recognises the phenomenon in their meta-analysis on the global burden of disease of solar UV radiation exposure. In this, the effect is found to apply to prostate, breast, colon, ovarian, and other tumors.⁷ Comprehensive meta-analyses show very strong evidence of an inverse relationship between UVB exposure.⁸

2 PREMISES AND HYPOTHESES

Immunosurveillance or immunoediting is a recognised and established phenomenon.⁹ They involve both innate and adaptive immunity. Sunlight must inevitably produce nascent tumor antigens in the skin and circulating leucocytes in superficial vessels. These are cleared by the immune system in communication with the central immune system including the lymph nodes. This results in adaptive immunity to some tumor antigens. This immunity is distributed throughout the body, in the same manner that immunity to a pathogen or via vaccine is distributed throughout the body, and is not solely localised to the sight of initial contact. There are antigens that are common to cancers irrespective of tissue of origin. This immunity to tumor antigens, generated in the skin, must therefore provide immunity to similar tumor antigens, were they to develop in other tissues. Extrapolating from this, increasing sunlight exposure increases neo-tumor antigenic generation and clearance and thereby increases adaptive immunity to a greater range of tumor antigens. Hence, increasing sunlight exposure, as a further necessary sequitur, must reduce the risk of cancer via this process of “heliovaccination” (Figure 1).

Figure 1

UV light produces mutations and subsequent tumor and pre-tumor antigens. These cells are attacked and cleared initially by innate immunity including natural killer (NK cells). Tumor antigens are phagocytosed and presented to peripheral or lymph node helper (TH) and cytotoxic (CD8+) T cells by antigen-presenting cells (APC). TH cells prime naïve B cells to produce antibodies (Y). A subset of these T cells and B cells form immunological memory. This facilitates the eradication of the tumor antigen should they occur anywhere in the body. This is analogous to vaccines administered in the skin conferring immunity irrespective of the origin of attack. For example, the BCG vaccine administered in skin protects against TB

2.1 Early life exposure and the risk of cancer: childhood heliovaccination?

The collateral evidence is very strong. Consistent with the vaccination hypothesis, one would anticipate that childhood or early life exposure would protect against tumor. Large international studies have shown very strong protective effects of childhood exposures, even under 10 years of age, to UV light on adult cancer. These include lymphoma,^10-14 breast cancer,¹⁵ prostate cancer,^16-18 oesophageal cancer¹⁹ and pancreatic cancer.²⁰

The primacy of the vitamin D hypothesis may have meant that in many cases the independent effect of childhood exposure has not been fully explored in a number of tumor types. Further research may be warranted in this area.

Further experimental data have shown an oncoprotective effect of UV radiation independent of vitamin D. Rebel et al examined mice with a genetic susceptibility to intestinal tumors. One group enjoyed a vitamin D-enriched diet, and the second had a normal diet but was exposed to addition UV radiation. Both cohorts were compared to a control group. Intriguingly, only UV irradiation was associated with a reduction in the progression of tumors to malignancy. Vitamin D supplementation did not have this effect.²¹ UV radiation appears to prevent the manifestation of malignant tumor in a pathway potentially not contingent upon vitamin D.

2.2 UV-mediated mutations

Co-evolution of UV light with organisms for 3.5 billion years²² would suggest a permissive approach of DNA repair mechanisms to UV-mediated mutation as to allow the generation of mutant antigens and heliovaccination. This is the case. One cohort of enzyme, such as polymerase ι, performs “error-prone” DNA repair.²³ Further eutherian (placental) mammals who have the highest risk of invasive cancer,²⁴ due to the cancer cells co-opting the molecular software of placentation for the purpose of invasiveness and metastasis,²⁵ are the only species to lack the photolyase²⁶ enzyme, specifically designed for high fidelity and rapid repair of UV-mediated DNA mutations. Hence, the loss of photolyase potentially exposes the host to more UV-mediated premalignant antigens potentially counteracting the increased risk of placental pregnancy.

Interestingly, Baadsgaard et al and Cooper et al independently reported that UVB light potently induced the appearance of specific antigen-presenting cells to the skin.^{27, 28} This effect was only achieved following UVB irradiation. The wavelengths of maximum absorption for RNA and DNA fall within the UVB band.²⁹

2.3 Evidence of adaptive immunity

Mutations in proto-oncogenes or tumor suppressor genes are critical stages in tumorigenesis, conferring on otherwise normal cells, pathological longevity, immortality and invasiveness. Other genes while not germane to oncogenesis facilitate survival. These mutated genes produce abnormal proteins which constitute tumor antigens. Given there exist a finite number of such genes, tumors, irrespective of tissue origin, frequently express similar tumor antigens. For example, mutated proteins of TP53 gene, p53, are expressed in up to 50% of tumors and have been mooted as a target for immunotherapy.^{30, 31} Hence, according to heliovaccination tumor and pretumor antigens generated from UV irradiation, cleared by the immune surveillance, can impart immunity when similar antigens appear in other viscera.

One compelling argument for the heliovaccination hypothesis is the presence of anti-tumor antigen-specific immune responses in patients with no apparent history of tumor or tumor antigen exposure. This manifests in the form of tumor antigen-specific T cells and antibodies in healthy individuals. Gajewski in the review on the tumor microenvironment commented³²:

A major conundrum has been how it is possible that even a subset of patients can generate a spontaneous CD8+ T cell response against tumor-associated antigens, apparently in the absence of pathogen involvement

Fascinatingly, the first tumor antigen-specific T-cell response demonstrated was derived from a skin tumor mutant gene. Twenty-five years ago, Coulie et al showed CD8+ T cells from a patient with metastatic melanoma recognised mutated gene antigen, melanoma associated antigen (mutated)–1 (MUM1).³³ MUM1 antigen although originally found in the skin has been observed in host of different cancer including lymphoproliferative and testicular malignancies (http://www.cancerindex.org/geneweb/MUM1.htm).

Antigen-specific CD8+ T cells have been identified in well individuals for a suite of tumor antigens. Intriguingly, the tumor antigen-specific CD8+ T cell with the highest prevalence in healthy individuals targets a skin cancer, in this case a melanoma antigen. The MELAN-A antigen-targeted CD8+ T cell is found in an exceedingly high frequency even in a tumorous individuals. This is at a frequency of 1/10³ of the blood CD8+ T cells, which is 100‑fold to 1000‑fold greater than frequencies of naïve CD8+ T cells against other antigenic peptides.³⁴ MELAN-A is observed in a number of other tumors including adrenal, ovarian tumors and paragangliomas in addition to melanomas.³⁵

Following on from their seminal work on the discovery of the first tumor-specific antigens and antibodies, Coulie and van de Bruggen reviewing the evidence of tumor antigen-specific immune response state³⁶

We now believe that the usual procedures that involve the in vitro stimulation of T cells of cancer patients with the autologous tumour cell line do not activate naive cells but only activate memory T cells that result from a previous spontaneous response against the tumour…On the basis of these and other findings, it is now clear that most patients with melanoma produce a spontaneous T cell response against their tumour. In many patients, this attempt at eliminating the tumour evidently fails

3 HOW TO TEST THE HYPOTHESIS

Animal studies would involve exposing cancer-prone animals to differing degrees of UV exposure and correlating this with the incidence of cancer. Irradiation could occur early in life, and then, various tumor parameters were assayed in later life of the animals. These include tumor prevalence, size, invasiveness and metastases. This would require ethical approval. Specific animal models include FabplCre;Apc(15lox/+) mice prone to intestinal tumors ^{\* MERGEFORMAT},^21. and Eµ-Myc and MMTV-Myc transgenic mice are prone to B-cell lymphomas and mammary tumors, respectively, and thus could also be used to demonstrate the effect.³⁷ This would then engage the examination of a number of histiotypes.

4 CONCLUSION

Appleby in his seminal paper correlating UV exposure and cancer risk states in the final paragraph:

It is suggested that we may be able to reduce our cancer deaths by inducing a partial or complete immunity by exposure of suitable skin areas to sunlight or the proper artificial light rays of intensity and duration insufficient to produce an actual skin cancer. A closer study of the action of solar radiation on the body might well reveal the nature of cancer immunity.

One of the Holy Grails of science since the inception of human existence has been a cure for a cancer. The notion of a universal vaccine against a whole gamut of tumors was beyond the wildest and fantastical scientific imagination. It is therefore somewhat ironic that such a vaccine may have been literally staring us in the face for the last 250 000 years.

CONFLICTS OF INTERESTS

The authors have declared no conflicting interests.