Reframing How Physical Activity Reduces The Incidence of Clinically-Diagnosed Cancers: Appraising Exercise-Induced Immuno-Modulation As An Integral Mechanism

Abstract

Undertaking a high volume of physical activity is associated with reduced risk of a broad range of clinically diagnosed cancers. These findings, which imply that physical activity induces physiological changes that avert or suppress neoplastic activity, are supported by preclinical intervention studies in rodents demonstrating that structured regular exercise commonly represses tumour growth. In Part 1 of this review, we summarise epidemiology and preclinical evidence linking physical activity or regular structured exercise with reduced cancer risk or tumour growth. Despite abundant evidence that physical activity commonly exerts anti-cancer effects, the mechanism(s)-of-action responsible for these beneficial outcomes is undefined and remains subject to ongoing speculation. In Part 2, we outline why altered immune regulation from physical activity - specifically to T cells - is likely an integral mechanism. We do this by first explaining how physical activity appears to modulate the cancer immunoediting process. In doing so, we highlight that augmented elimination of immunogenic cancer cells predominantly leads to the containment of cancers in a 'precancerous' or 'covert' equilibrium state, thus reducing the incidence of clinically diagnosed cancers among physically active individuals. In seeking to understand how physical activity might augment T cell function to avert cancer outgrowth, in Part 3 we appraise how physical activity affects the determinants of a successful T cell response against immunogenic cancer cells. Using the cancer immunogram as a basis for this evaluation, we assess the effects of physical activity on: (i) general T cell status in blood, (ii) T cell infiltration to tissues, (iii) presence of immune checkpoints associated with T cell exhaustion and anergy, (iv) presence of inflammatory inhibitors of T cells and (v) presence of metabolic inhibitors of T cells. The extent to which physical activity alters these determinants to reduce the risk of clinically diagnosed cancers - and whether physical activity changes these determinants in an interconnected or unrelated manner - is unresolved. Accordingly, we analyse how physical activity might alter each determinant, and we show how these changes may interconnect to explain how physical activity alters T cell regulation to prevent cancer outgrowth.

Keywords: cancer; exercise; exercise immunology; exercise oncology; physical activity.

Figure 1

Association between the tumour mutational burden (TMB) of a cancer tissue location and the magnitude of risk reduction for that cancer site in the 90^th vs. 10^th percentile of self-report leisure-time physical activity. Cancer risk in the 90^th vs. 10^th percentile of physical activity data were obtained from ref (2). TMB data were obtained from ref (77). Blue triangles indicate cancer sites with a TMB below the median (<3.47 mutations per megabase) and black triangles indicate cancer sites with a TMB equal to or above the median (≥3.47 mutations per megabase). Associations between TMB and cancer risk in 90^th vs. 10^th percentile of physical activity were examined using Spearman’s r as data were not normally distributed (Shapiro-Wilk P>.05). Analysis was performed in Graph Pad Prizm v9.0.1 (GraphPad Software, California, USA). Melanoma was excluded from analysis due to established confounding effects of UV exposure on cancer risk associated with physical activity. TMB data from ref (77) included multiple different cancer subtypes within a given tissue location. The TMB of relevant cancer subtypes was calculated for each of the cancers reported in ref (2), guided by the International Classification of Diseases for Oncology 3rd Edition, as per Supplemental Table 3 in ref (2). This calculation was adjusted to control for the frequency of samples (per cancer subtype) analysed in ref (77), in an attempt to adjust for the relative incidence of different cancer subtypes among the general population. Nevertheless, a limitation of this approach remains an assumption that different cancer subtypes – which commonly varied in TMB – were equally represented in the sampling of ref (2) and ref (77).

Figure 2

A synthesis of possible candidate mechanisms explaining how T cell regulation is augmented by physical activity leading to enhanced T cell function against tumour cells, culminating in the preservation of cancers in the equilibrium phase of the immunoediting process. In this hypothetical process, we illustrate how regular exercise might alter features of T cell success contained within the cancer immunogram, which in turn may explain how regular exercise maintains immune control of immunogenic tumours. Each candidate component is driven by the effects of immunoregulatory cytokines (e.g., IL-7, IL-15), secreted from skeletal muscle in people who are physically active, on immune competency. The candidate components included in this model are: (1) Physical activity may alter general T cell status in blood by preserving naïve T cell frequency in ageing, thus enabling T cells to identify a greater diversity of tumour antigens in older age. As outlined in Determinant 1 however, we note that there is not conclusive evidence yet that naïve T cell output is maintained by physical activity in ageing. Instead, following antigen encounter, regular exercise may revert antigen-experienced memory T cells and preserve these as stem cell-like cells such as T_NRM cells and T_SCM cells, with a surface phenotype similar to naïve T cells. This maintenance of stem cell-like T cells (such as T_SCM and T_NRM cells) may augment the supplementation of tissue-associated memory T cells, thus leading to more persistent anti-tumour responses when required. (2) Acute exercise may augment the redistribution and infiltration of CD8⁺ T_EFF cells, as well as other T cell subsets, to tissue sites harbouring tumour antigens. However, as outlined in Determinant 2, we note that there are incompatibilities in the theory that exercise acutely mobilises effector cells to sites harbouring tumours. (3) Regular exercise may alter immune checkpoint expression, by preferentially suppressing development of CD4⁺ T_REG cells in tissue sites harbouring tumour antigens, averting T cell anergy and leading to more robust effector responses against cancer cells. In addition, regular exercise may reverse exhaustion to PD1⁺ stem cell-like CD8⁺ T cells – upon chronic exposure to antigen and immunosuppressive cytokines – which may help supplement the frequency of tissue-associated memory T cells with capacity to elicit persistent effector responses. (4) In tandem to Determinant 3, regular exercise may alter the presence of inflammatory mediators within the tumour microenvironment – namely IL-10 and TGF-β – by suppressing the development of T_REG vs. T_EFF, thus alleviating immunosuppressive signalling within the tumour microenviornment to enhance T cell killing of cancer cells. (5) Exercise training may alter metabolic inhibitors of T cell activity within the tumour microenvironment, via the enhancements to immune competency discussed in Determinants 1-3, which increase T cell killing of cancer cells to reduce lactate accumulation, acidosis, and hypoxia which arise from the tumour cells themselves. Importantly, each component in this model is dependent on tumour-intrinsic factors: (A) immunogenicity (i.e., tumour ‘foreignness’), and (B) MHC-1 expression (i.e., ‘visibility’), and therefore the anti-cancer benefits of physical activity are unlikely to be seen in the absence of tumour immunogenicity and MHC-1 expression. T_REG cells, Regulatory T cells; T_EFF cells, Effector T cells; T_SCM cells, Stem-like T cells; T_NRM cells, Naïve-revertant memory T cells. Created with BioRender.com.