**4. Conclusions**

102 Topics in Cancer Survivorship

which predict the 2, 4, and 6 year mortality rates. Immune risk profiles (IRP) mainly include

Age-associated immunosenescence (>85 years)

It has been suggested that age-related dysfunction may not be the sole cause of immunosenescence, but the presence of an infectious component appears to be the force driving T cells towards senescence. Pawelec et al. has proposed that CMV infection is responsible for the development of immunosenescence in the elderly, not aging per se (Pawelec et al., 2006). The inflame-aging hypothesis in human ageing proposed by Franceschi et al. also suggests that immunosenescence is mainly driven by the chronic viral antigen stimulation (Franceschi et al., 2000). Repeated CMV infection induces significant expansion of late differentiated-stage of CD28-CD8 effector cells, leading to alteration of homeostatic T-cell (i.e., inverted CD4/CD8 ratio and T-cell subpopulations, etc.). An analysis of immunosenescence data revealed that elderly individuals had a decreased number of naïve T cells and an increased number of effector/memory and effector CD8 T cells compared to young individuals; however, both had a similar amount of TCM cells. Such large expansion would not only limit the number of clonal expansions of CMV-specific T cells but also result in shrinkage of clonal diversity (Hadrup et al., 2006; Pawelec et al., 2004). Thus, it is not surprising that old people have increased susceptibility to pathogens. The CMV-specific CD28-CD8 effector cells can secret IL-6 cytokine that prolong inflammatory activity during pathogen infections (O'Mahony et al., 1998). The increased levels of circulating IL-6 would potentially induce CRP that is significantly correlated with mortality of elderly (Krabbe et al., 2004; Wikby et al., 2006). Patients with cancer are more vulnerable than healthy individuals to have CMV reactivation. In fact, the immune status of cancer patients is very similar to IRP seen in the elderly. Our previous data have shown that

CD4/CD8 ratio - - Naïve T cells - - Memory T cells + + CD28- T cells + + CMV-specific T cells + + IL-7R Possible- - IL-6 + + CMV viral load + + Table 1. Comparison of the immune profiles in age-associated immunosenescence and aggressively treated cancer patients. +, increase; -, decrease. aPatients with various types of cancer were enrolled in the Mackay Memorial Hospital. None of the patients had received immunotherapy when the blood samples were collected, but all had received chemotherapy according to the standard treatment regimen for their specific cancer (Chen et al., 2010).

Aggressively treated cancer patientsa (45–75 years)

(Ferguson et al., 1995; Pawelec et al., 2004; Pawelec et al., 2006; Wikby et al., 1998):

i. inverted CD4/CD8 ratio, ii. poor T-cell proliferative activity,

iv. persistent CMV infection,

CD8 T cells,

v. clonal expansion of dysfunctional CMV-specific CD8 T cells.

iii. increased CD28-

In summary, we propose that patients with advanced cancer who received extensive treatment have an accelerated immunosenescence that may be clinically relevant for cancer treatment. Typically, there is a decrease in naïve and TCM cells, but an increase in the proliferation and differentiation of the TEM population. The immune impairment in these patients is associated with multiple factors such as the stage of cancer, impact of treatment schedules, and consequence of CMV reactivation. It has been suggested that, with aging, CMV-specific effector T cells accumulate in such large numbers that they may be the dominant T-cell population in the peripheral blood of healthy elderly individuals. These Tcells are found to be specific for fewer epitope of CMV (Pawelec et al., 2005).

In addition, CMV infection may induce a decrease in T-cell telomere length and lead to a shift in the composition of the T-cell pool (van de Berg et al., 2010). The deleterious effect of CMV persistence on the human immune system is usually insidious and requires decades to be recognized. By contrast, the immune systems of cancer patients are somehow rapidly driven to an analogous state of immunosenescence. Therefore, it is conceivable that patients who receive extensive chemotherapy would have a greater risk of repeated CMV exposure, leading to the accumulation of CMV-specific immune cells. The clonal expansion of CMVspecific T cells may thus shrink the repertoire of immune cells available for other antigens and result in the chemotherapy-associated deterioration of immune function.

With a more complete understanding of the immune profile of cancer patients, clinical investigators will be able to provide strategies to restore a robust immune response in the tumor-bearing host (active tumor immunity) or, alternatively, promote immunity by the adoptive transfer of activated effector cells or tumor-specific antibodies into the tumorbearing host (passive tumor immunity). In addition, certain biomarkers, such as the T-cell subpopulations, IL-7R, CD28, IL-6, CMV-specific T cells, CMV-specific IgG, and CMV viral load, may be useful for monitoring the immune status of patients during, or more importantly, before cancer treatment. Since CMV reactivation may in turn serve as the driving force for generating virus-specific T cells rather than tumor-specific T cells, we propose that even latent CMV infection may contribute to the immune tolerance of tumors. This raises the intriguing possibility that preemptive anti-CMV treatment could be an important adjunct in cancer treatment, especially during chemotherapy. Without consistent antigenic stimulation, TEM cells undergo apoptosis, resulting in a decrease in this cell population and an increase in committed effector cells. Prevention of CMV reactivation

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**8** 

Duclos Martine

*France* 

**Physical Activity and Cancer:** 

*Hopital G. Montpied, Clermont-Ferrand 2 INRA, UMR 1019, Clermont-Ferrand* 

*4CRNH-Auvergne, Clermont-Ferrand* 

**It is Never Too Late to Get Moving!** 

*3University Clermont 1, UFR Médecine, Clermont-Ferrand* 

*1Department of Sport Medicine and Functional Explorations, University-Hospital (CHU),* 

In terms of prevalence, the most common cancers in men and women worldwide are breast cancer (3.9 million breast cancer cases) and colorectal cancers (2.4 million). Moreover, the worldwide incidence of breast and colorectal cancers is destined to increase substantially in the next few decades. Therefore, the prevention of the occurrence of these various types of cancers represents a real stake in public health for which physical activity could play an important role. Indeed, numerous studies showing an association between prevention of

The number of survivors after treatment of a cancer ("cancer survivors") is also increasing. Since last years, different studies have rocked the research community involved in cancer survivorship. These studies reported a significant protective association between increased physical activity that occurred after the diagnosis of breast or colon cancer and recurrence, cancer-related mortality, and overall mortality among breast cancer or colon cancer

This chapter will consider epidemiologic evidence regarding the association between physical activity and breast and colon cancer in primary prevention (cancer occurrence) and in tertiary prevention (cancer recurrence). The second aim of this chapter will be to discuss the type and characteristics (duration, intensity) of physical activity associated with these effects both in primary prevention of breast and colon cancer and in cancer survivors. In

Evidence for the underlying mechanistic targets of physical activity interventions on the carcinogenesis process is also emerging. Studies suggest that exercise can exert its cancerpreventive effects at many stages during the process of carcinogenesis, including both tumour initiation and progression. This will be discussed in the third part of this chapter. In the fourth part, the barriers to prescribe physical activity in physicians will be discussed as the published work provides sufficient evidence to suggest that physical activity is safe and well-tolerated even in cancer survivors and that oncologists can recommend to their patients physical activity after the completion of primary treatment. Finally we will discuss

these cancers and physical activity have been published these last years.

other words, what types of exercise are most beneficial?

**1. Introduction** 

survivors.

