Epidemiologic perspective on immune-surveillance in cancer

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Common ‘themes’ in epidemiology related to cancer risk beg a comprehensive mechanistic explanation. As people age, risk for cancer increases. Obesity and smoking increase the risk for many types of cancer. History of febrile childhood diseases lowers the risk for melanomas, leukemias, non-Hodgkin's lymphoma (NHL), and ovarian cancer. Increasing number of ovulatory cycles uninterrupted by pregnancies correlate positively with breast, endometrial, and ovarian cancer risk while pregnancies and breastfeeding lower the risk for these cancers as well as cancers of the colon, lung, pancreas, and NHL. Chronic inflammatory events such as endometriosis or mucosal exposure to talc increase the risk for several types of cancer. Mechanisms so far considered are site specific and do not explain multiple associations. We propose that most of these events affect cancer immunosurveillance by changing the balance between an effective immune response and immune tolerance of an emerging cancer. We review recently published data that suggest that immune mechanisms underlie most of these observed epidemiologic associations with cancer risk.

Research highlights

▶ There are common themes in cancer epidemiology that beg comprehensive explanations. ▶ Age, smoking, obesity, and other events could operate through immune surveillance. ▶ Exposure of the immune system to cellular proteins may underline an immune mechanism.

Introduction

Cancer is a threat to the survival of an organism and needs to be recognized early and reckoned with. The immune system has been invoked many times as a likely mechanism for keeping cancer under control but experimental techniques and animal models that could unambiguously show and test its role in cancer control were not available. Eventually, however, numerous molecules on human cancer cells or in animal models of cancer were discovered capable of triggering immunity (tumor associated antigens) and serving as targets of an immune response for tumor destruction. Immunosurveillance as a natural defense mechanism is now widely accepted but the definition has been broadened to include many different interactions between the immune system and cancer, including cancer elimination, long-lasting equilibrium, tumor escape, and tumor promotion [1, 2, 3].

Because even the best and the newest mouse models cannot fully replicate human disease, and because of significant differences between the human and the mouse immune systems, the life-long protective or promoting effects of immunity on cancer and the factors that determine and modulate anti-cancer immunity need to be studied in humans. Since the experimental studies performed in animals generally cannot be duplicated in humans, ‘natural experiments’ are necessary in which past experiences of individual with and without cancer are compared or cohorts of persons with and without particular exposures are followed for the occurrence of cancer. These types of studies have revealed a number of common themes in cancer epidemiology. Risks for many types of cancer increase with aging, smoking, and obesity. History of febrile childhood infections, on the contrary, may actually lower the risk for certain adult cancers including ovarian cancer and non-Hodgkin's lymphoma (NHL). In women, pregnancies and breastfeeding lower the risk for breast, endometrial, and ovarian cancers as well as cancers in ‘non-reproductive’ organs such as colon, lung, and pancreas and NHL. Conversely, chronic inflammatory diseases like endometriosis or an increasing number of ovulatory cycles that have not been interrupted by pregnancies, breastfeeding, and oral contraceptive use correlate with increased breast, endometrial, and ovarian cancer risk. Proposed mechanisms that might govern these associations are often site specific and do not explain multiple associations. In this review we will present accumulating evidence that most events that epidemiologists have associated with a higher or a lower cancer risk affect the immune system; and thus effective versus ineffective immunosurveillance may be the unifying mechanisms underlying all these different associations.

Section snippets

Immunosenescence: immune mechanism behind epidemiological associations between age and cancer

About 60% of all cancers occur in people age 65 or older [4]. With the obvious exception of childhood cancer, age specific incidence (i.e. number of cancer cases in a particular age group divided by the population in that age group) increases with age. Epidemiologically, this phenomenon can be demonstrated by plotting log of incidence against log of age and demonstrating a straight line with a positive slope [5]. Some cancers for which this linear pattern is most evident include prostate,

Chronic inflammation: immune mechanism behind epidemiological associations between obesity and cancer

Obesity is associated with approximately 14% of cancer deaths in men and 20% of cancer deaths in women [10]. Risk for colorectal, esophageal, gallbladder, renal, pancreas cancers, myeloma, and NHL is increased with body mass in both men and women. In obese women, risk for postmenopausal breast cancer and endometrial cancer is increased, while in men, obesity is associated with a more aggressive form of prostate cancer [11]. Multiple site-specific mechanisms have been proposed. For example,

Immune mechanisms modulating cancer risk from smoking

Smoking is the leading cause of cancer and deaths from cancer. From a comprehensive review by the Centers for Disease Control and Prevention (CDCP), there is consistent evidence that smoking increases the risk for cancers of the lung, esophagus, larynx, mouth, throat, kidney, bladder, pancreas, stomach, and uterine cervix, as well as acute myeloid leukemia [16]. Additional epidemiologic evidence suggests that smoking (or smokeless tobacco) may also increase the risk for colorectal cancer [17],

Childhood illnesses and cancer immunosurveillance

The role of childhood infections in childhood cancers has been examined in epidemiologic studies looking for cancer clusters among children. A study in England identified several higher than expected clusters and concluded that measles might have occurred 2–3 years before the onset of leukemia in close pairs of affected children [23]. On the contrary, another study found that larger sibship size, greater household crowding, and occurrence of childhood infections lowered the risk for childhood

Reproductive events, cancer risk, and immunosurveillance

Pregnancies and breastfeeding are known to reduce the risk for breast, ovarian, and endometrial cancer [44, 45, 46, 47]. Oral contraceptives (OC) also substantially reduce the risk of ovarian and endometrial cancer but an effect on breast cancer is less clear [48, 49, 50]. Explanations are, again, site-specific and include terminal differentiation of breast tissue with pregnancy and breastfeeding for breast cancer; protection from the harmful effects of ovulation for ovarian cancer; and

Conclusion

We have reviewed the most recent studies that implicate the immune response as a unifying and non-site specific determinant (both positive and negative) of cancer risk. Antibodies and T cells to numerous abnormally expressed self molecules on tumor cells (tumor associated antigens) have been detected in cancer patients and some have been associated with better prognosis [63, 64••]. The most abundant data exist on the humoral immune responses against tumor-associated antigens (TAA). A recent

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors gratefully acknowledge NCI support for their collaborative studies under the RO1CA054419 (D.W.C.) with added support from P50CA105009 (D.W.C.) and PO1073743 (O.J.F.).

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